In a 2015, retrospective single-center study, patients with advanced HCC received systemic therapy with sorafenib combined with transarterial chemoembolization (TACE), and outcomes were compared between elderly (>70 years) and nonelderly (<70 years) patients.
Pierre M. Gholam, MD
The elderly constitute an important population of patients with unresectable hepatocellular carcinoma (HCC). In a 2015, retrospective single-center study, patients with advanced HCC received systemic therapy with sorafenib combined with transarterial chemoembolization (TACE), and outcomes were compared between elderly (>70 years) and nonelderly (<70 years) patients. These investigators found a similar benefit of the intervention, with similar tolerability, in the both subgroups.
Targeted Oncologyspoke with Pierre M. Gholam, MD, medical director at the Liver Center of Excellence and Digestive Health Institute at University Hospitals Case Medical Center, and associate professor of medicine at the Division of Gastroenterology and Liver Disease, Case Western Reserve University School of Medicine.
Q: Why is the management of unresectable HCC, particularly in elderly patients, becoming an increasingly important issue?
A: The three options that we know can cure HCC are resection for cure, or R0 resection, liver transplantation, in patients who have limited diseaseusually patients who meet the Milan criteria—and radiofrequency ablation, for solitary lesions less than 2 cm. For everyone else who does not undergo one of those three [options], the goals are to improve survival and quality of life. About 80% of patients in most Western populations have what we would describe as unresectable HCC, so the bulk of patients who come into care are not amenable to definitive therapies, including resection or liver transplantation. However, these patients still need treatment options that can help them have better quality, and quantity, of life.
The mean age of diagnosis for HCC, across the board, in studies that are typically conducted in the West, is somewhere between 60 and 65 yearsso to begin with, the average age of a person with HCC is usually in the sixties by the time they are diagnosed. Based on our own database, easily about 30% of patients are over the age of 70 years, so a large number of those patients would be considered elderly by any definition. In addition, patients usually take a while to develop HCC. If you take a patient with cirrhosis, their average risk of developing HCC if they have hepatitis C, which is the most common cause of cirrhosis in the United States, would be 3% to 5% per year. Therefore, it would take them more than a decade to have a substantial cumulative risk of developing HCC. This is a process that takes time, beyond the initial time it takes patients to develop cirrhosis, which typically is anywhere between 3 to 4 decades. It’s therefore not surprising that patients develop HCC later in life. Another reason is the fact that we now have better tools and medications to make patients with cirrhosis live longer, and as they live longer, they have a greater statistical chance of developing HCC over time, because of this ongoing risk factor.
Q: What are the principal palliative options for elderly patients with unresectable HCC?
A: For patients who have small lesions (<3 cm, and in most cases <2 cm), and a limited number of lesions, radiofrequency ablation is not an unreasonable option. I should also say that radiofrequency ablation was the dominant modality up until the past 5 to 10 years, and is now being challenged by other tumor destruction modalities that achieve the same goal, but are not actually ‘heat’ applications. These include cryotherapy, which is performed in some centers, but mainly microwave coagulation therapy, which has become fairly common among our own interventional radiologists. I would call these direct tumor destruction therapies by application of heat, cold, or microwave energy. So this would be one option, for small lesions that are limited in number.
For lesions that are bigger, typically >3 cm, or if you have more than one of these, and the patient is not otherwise a candidate for liver transplantation, the dominant treatment modality is in the form of catheter mediated interventions. These come in two [main types], transarterial chemoembolization, where chemotherapy is injected into the tumor followed by an embolic process, or the administration of radiotherapy to tumors in a similar manner, through the application of Yttrium-90 loaded glass beads that can also be injected into tumors to achieve a very potent, but localized irradiation effect in the tumor. These modalities apply to many patients with unresectable cancer, but one of the main limitations is that there is a finite failure rate, or lack of response, and unfortunately we do not have great tools to tell us when these treatments fail. So even though you might follow up with an MRI, or some type of dynamic imaging test after procedure is performed, our ability to determine the response rateeven with good imaging—remains somewhat limited. So we often end up, potentially, continuing to treat patients when they are destined not to respond to these therapies.
Q: How does systemic therapy factor into the treatment options?
A: Systemic therapy, by most treatment algorithms that are available today, including the Barcelona Clinic Liver Classification, is unfortunately relegated to a fairly advanced stage of diseaseusually a disease in which there is macrovascular invasion or extrahepatic spread—and after locoregional therapies have failed. There is a general feeling among experts that this may be a delay of therapy that is not helpful. So, patients may potentially be helped by undergoing systemic therapy at an earlier stage or at the earliest inkling that local therapy might not be working. Systemic therapies are generally used after you’ve tried local treatments, or if the patient is diagnosed from the start at a BCLC Stage C disease or greater. So for many patients [systemic] therapy is, unfortunately, delayed, when in fact there may be a significant potential for benefit, based on the data that led to the approval of sorafenib, which is the only systemic therapy that is currently FDA approved. I think, increasingly, people understand the potential benefit, and are more aggressive about treating patients with systemic therapy at an earlier stage than some of the treatment algorithms suggest.
Q: What is the role of combining systemic treatment with local therapy in the treatment of unresectable HCC?
A: The idea of combining locoregional therapy with systemic therapy is not new; there have now been a number of studies looking to see whether or not there is incremental or additional benefit to combining both modalities. Some of these have been single center, or a few have been center studies, and some have been large randomized studies (ie, the SPACE study). What these have shown is that, although this approach appears to be quite safe, and does not lead to significant incremental toxicity, it is difficult to prove that combination therapy is superior to monotherapy. The reasons for that are multiple, but I think most would agree that it [the reason] is largely related to the way studies are designed and conducted. It appears that the application of locoregional therapy, primarily TACE, does not appear to happen at the same interval of time, and based on the same parameters, across different study sites, so that you can actually compare things in a systematic way.
Q: What is your impression of recent retrospective data from Hu et al (2015) suggesting similar survival in elderly and non-elderly patients with sorafenib and TACE?
A: This study basically looks at the combination of TACE with sorafenib in a group of patients aged>70 years compared with patients aged less than 70 years. What it does show, in this particular case, is that there do not appear to be differences in survival between elderly and nonelderly patients. It does also show that if you take an elderly population in isolation, there does not appear to be any significant decrement in effectiveness, or increase in toxicity, compared with patients who are younger. So it [the study] does provide some reassurance that if we actually do treat this growing population of elderly patients, we would likely be able to do so without major concerns about safety, and hopefully [we could] expect more or less the same results in that population as we would in a general population.
Of course this is retrospective, so you are not doing this in a prospective manner to have the same rigor in determining whether or not this is truly a therapy effect, as opposed to a by-product of retrospective study bias; so this is one major limitation. Also, this was exclusively an Asian population, and the drivers behind HCC in Asia and the West are different, and in this particular case, the overwhelming majority of patients had hepatitis B (HBV). However, in most Western populations, hepatitis C (HCV), and to a lesser extent, alcohol and fatty liver disease, would be the main drivers. Many of the patients in the study did not have cirrhosis as is typical of populations where HBV infection is the main driver behind HCC. In addition, patients who receive TACE in Asia tend to be sicker and generally have undergone more aggressive surgical therapy compared with Western populations.
Hu H, Duan Z, Long X, et al. Comparison of treatment safety and patient survival in elderly versus nonelderly patients with advanced hepatocellular carcinoma receiving sorafenib combined with transarterial chemoembolization: a propensity score matching study. PLoS One. 2015;10(2):e0117168. doi: 10.1371/journal.pone.0117168.