Hepatocellular carcinoma (HCC) is a global problem and the second most common cause of cancer-related deaths in the world. Its global incidence has been reported to be on the rise and is predicted to exceed one million cases per year by 2025. In a recent review, published in the Journal of Hepatology, Mayo Clinic researchers examined the clinical implications of current basic research in HCC.
Currently, the overall survival of patients with HCC is bleak: less than 15% will live more than five years. This is largely due to the fact that a majority of HCCs are diagnosed at advanced stages when patients are not eligible for curative therapies such as resection or transplantation. And, advanced HCCs are resistant to most standard chemotherapy regimens.
Why is HCC more often diagnosed at an advanced stage?
“The liver is a large, soft organ hidden away in our body, behind the ribs, to protect it from injury,” says Lewis Roberts, M.B., Ch.B., Ph.D., hepatologist at Mayo Clinic and senior author of the paper. “Consequently, the places where tumors develop are not obvious.”
Also, the liver in itself does not have any nerve fibers. The only nerve fibers are in the lining around the liver. This means a tumor can grow quite large within the liver without causing any pain.
“Unless we’re on the lookout for individuals who are at risk for liver cancer and place them on a program where we’re checking their livers on a regular basis, it’s most likely that we will not discover a tumor until a very late stage, when the tumor begins to stretch the lining of the liver,” says Dr. Roberts. “Only then do people begin to experience pain.”
The first systemic drug to be approved for the management of advanced HCC was sorafenib. But this prescription drug only increases survival by a modest three months and can have severe side effects.
In the past few years, on the heels of sorafenib, several other new drugs have emerged. But they failed in phase III trials for HCC. This reinforces an urgent need to find other approaches or drugs that are better than sorafenib while not having worse side effects.
Another critical challenge faced by clinicians managing patients with HCC is the heterogeneity of this cancer, both at a morphologic and a molecular level. Every liver tumor has its own unique characteristics.
“If we think of them broadly, there are some liver cancers that start as a single spot or mass and, by their very nature, tend not to spread but slowly increase in size over time,” notes Dr. Roberts. “At the other end of the spectrum are tumors that are inclined to spread and metastasize. These tumors are highly aggressive, highly metastatic. Then, you have everything in between. Also, different portions of the liver cancer might have a different genetic makeup.”
This heterogeneity needs to be addressed with a more individualistic approach as clinical trials move forward. If a new drug’s effectiveness is to be fully tested, patients in a trial group should, correspondingly, all have a higher expression of that particular drug’s “target gene.” However, many trial groups often consist of patients with varying expressions of the target gene, and yet, they are all being treated the same way, with the same drug(s).
“People may have no response to a trial drug because they may have very low expression of the target gene,” says Dr. Roberts. “Alternately, a drug may be ineffective because several different gene targets are represented among those receiving the treatment drug.”
Fortunately, according to the review, this is all beginning to change. Multiple biomarkers that predict response to sorafenib therapy are now being described and, with further validation, these may serve as useful tools for patient selection. Importantly, the promising findings of a new drug called tivantinib, which was more effective for tumors that expressed high levels of its target gene c-MET, raise hope for improved results from future biomarker-enriched clinical trials.
“Once we’re able to show tivantinib’s effectiveness,” says Dr. Roberts, “then we’ll start thinking about combining it with sorafenib, or combining it with other types of medications as well to increase effectiveness and delay development of resistance.”
There are also recent indications that a group of drugs called immune checkpoint inhibitors, which block the ability of liver cancers to evade recognition by the immune system, will prove particularly effective against liver cancer.
Echoing the review’s overall conclusion, Dr. Roberts says, “I think there is a lot of hope that we’ll see improvements.”