The ASCO Annual Meeting is always packed with the latest and greatest advances in the field of oncology, and this year was no exception! The 2015 meeting had posted record-breaking numbers for abstract submissions and attendance, with over 37,000 individuals crowding the halls of the McCormick Place in Chicago.

One of the most popular presentations at the meeting focused on the impressive activity of immuno-oncology in hepatocellular carcinoma (HCC). This important study found that the PD-1 inhibitor nivolumab (Opdivo) could effectively shrink tumors for patients with pretreated HCC without inducing substantial side effects.

In this phase I/II study, the 19% prolonged objective response rate (ORR) with nivolumab is encouraging, and offers the potential of a novel treatment modality for HCC. Importantly, nivolumab was effective in patients with viral hepatitis and those with underlying liver cirrhosis, marking an important advance that is desperately needed for patients with limited options.

Exciting data for other novel agents were also presented at the Meeting. Another checkpoint inhibitor, tremelimumab, showed an ORR of 40% in combination with chemoembolization or radiofrequency ablation in pretreated HCC. Additionally, the antibody TRC105 plus sorafenib and axitinib with chemoembolization showed high responses in two separate early phase clinical trials.

While these findings are exciting for patients with advanced disease, the focus remains on early detection and improvements to curative surgical strategies. Additionally, HCC prevention remains an important factor, especially with novel therapies that are revolutionizing the treatment of hepatitis C, according to Michael P. Manns, MD (

Click here, to see more from this interview

With the host of evolving therapies, potential prevention strategies, growing curative options, and improved surveillance modalities, the future for HCC looks bright. I look forward to larger investigations and validation studies as we move closer to eradicating this disease.

Articles

Clinical Articles

Immuno-Oncology Arrives in HCC

Novel agents that target the replication of the hepatitis C virus are poised to have a far-reaching impact on the prevention and recurrence of hepatocellular carcinoma (HCC). This impact could be far-reaching, since in North America the primary risk factor for HCC is hepatitis C virus infection, which leads to the disease in approximately 50% of patients. In other countries this rate fluctuates, reaching 65% in Japan and closer to 20% in Asia and Europe.

As the leading cause of HCC, novel treatments for hepatitis C can have a dramatic impact on the incidence of the disease and potential treatment strategies. In a recent keynote presentation at the 2015 World Congress on GI Cancer, Michael P. Manns, MD, noted that the goal in 10 to 20 years is to have no more liver transplantation due to hepatitis C virus-positive HCC. Additionally, Mann hopes that in the future there will no longer be hepatitis C-associated liver cancer, which he said could only be realized through global access to novel therapies, like simeprevir (Olysio) and sofosbuvir (Sovaldi).

For further insight into the relationship between advances in hepatitis C care and the future of HCC treatment,

spoke with Manns, director, Department of Gastroenterology, Hepatology, and Endocrinology, Medical School of Hannover in Germany, at the World GI Congress.

: Prevention is key. We know that preventing or reversing cirrhosis is the best way to prevent liver cancer development. Once it occurs, we need to treat the early stages by locoregional therapies or surgery. Then, clearance of the hepatitis C virus should be significant in reducing the risk of recurrent disease. If you cure the virus before cirrhosis develops, that is key. Finally, we need to eradicate the hepatitis C entirely and that may be difficult without a vaccine, but we are on the right track. Another issue in hepatitis C prevention is accessibility and cost. However, the building blocks to solve this are available.

How has the treatment of hepatitis C changed in recent years?

Previous treatment for hepatitis C, which was mostly limited to ribavirin and interferon, was 1-year long and full of side effects and drug interactions with HCC treatments. Now, the new direct-acting antiviral agents have high cure rates of more than 90%, almost no side effects, and only take on an average of 12 weeks to administer.

It is interesting to see how fast the field of hepatitis C is moving. Most of the data are still from the interferon days, so we need to really revaluate everything, especially since these new agents and combinations have been approved.

What questions remain unanswered in the treatment of hepatitis C&shy;associated liver cancer?

For patients who can receive curable therapies for hepatitis C who already have HCC, clearing the virus reduces the risk of recurrent disease. However, we are missing data for patients in palliative treatment for advanced disease. We are unsure of the impact clearing hepatitis C in that population has on liver cancer.

Moreover, it is important to take note of patients with hepatitis C who receive a transplant. In the past, reinfection has been universal, and recurrent hepatitis C had very inferior outcomes compared to other indications for liver transplantation. Therefore, the first goal should be to get the hepatitis C population after transplantation free of hepatitis C and prevent reinfection.

We need to determine whether and to what extent hepatitis C treatment can prevent cancer. This is particularly relevant in those with liver cirrhosis. In the past, this was easier to prove because only half of those treated for hepatitis C responded to treatment and we could compare responders to nonresponders. Now with cure rates at almost 90% for hepatitis C, we have very few nonresponders. Therefore, the control group would be hard to find. It is unethical to not treat for hepatitis C, so I think treating for hepatitis C will be recommended in the future. The message should be: if you clear the virus, the risk of liver cancer is significantly reduced.

We may need to develop new strategies for surveillance of patients who have been treated for hepatitis C. We know that increased age is associated with risk of having high-alpha one fetoprotein.

Are there patients with HCC who should not be treated for hepatitis C?

If the HCC prognosis is very inferior and survival is not likely, then treating for hepatitis C may not be beneficial. We do not know if treating hepatitis C could be detrimental to some patients at this time, so that is something that needs to be considered with each advanced patient.

Novel agents that target the replication of the hepatitis C virus are poised to have a far-reaching impact on the prevention and recurrence of hepatocellular carcinoma (HCC). 

Novel Hepatitis C Treatments Impact HCC Care:  Q&A With Michael P. Manns, MD

A collection of early phase clinical trials presented at the 2015 ASCO Annual Meeting demonstrated promising results for several novel agents in combination with established treatments for patients with hepatocellular carcinoma (HCC).

In a phase I/II study, the chimeric IgG1 anti-CD105 monoclonal antibody TRC105 was explored in combination with sorafenib for patients with HCC who did not respond to other therapies and were not candidates for transplantation. The study enrolled 21 patients, with 19 evaluable at the analysis. Twelve patients had cirrhosis of the liver, additionally 2 had hepatitis B and 10 had hepatitis C. TRC105 was administered at 3, 6, 10, and 15 mg/kg every 2 weeks and sorafenib was administered at 400mg twice daily.

The most frequently reported adverse event (AE) was low-grade epistaxis. At the 10-mg/kg dose, a dose limiting increase in AST was observed. However, in the ongoing study, a 15-mg/kg dose of TRC105 will be explored (NCT01306058).

In 16 patients who were evaluable for response, the objective response rate (ORR) was 25%, which was comprised entirely of partial responses. At the 15-mg/kg dose, the ORR was 50%. Across all doses, 4 patients (25%) had stable disease and the median progression-free survival (PFS) was 4.1 months. At the 15-mg/kg dose, the median PFS was 5 months.

Checkpoint Inhibitor Tremelimumab Effective

A 20-patient pilot study examined the antiCTLA-4 monoclonal antibody tremelimumab in combination with transcatheter arterial chemoembolization (TACE) or radiofrequency ablation (RFA) in patients with HCC. Cirrhosis was detected in 13 patients, with hepatitis B positivity found in 4 patients and hepatitis C in 10 patients. All patients were sorafenib-refractory or -intolerant.

During treatment with tremelimumab, 8 patients received TACE and 10 underwent RFA. Across both arms, dose limiting toxicities were not observed. The most common AE was pruritus, which is common with immunotherapies. In the study, 1 patient developed pulmonitis and discontinued therapy. However, this individual remains disease-free at 16 months.

In the full evaluable population (n = 17), the median PFS was 7.4 months. All evaluable patients demonstrated immune cell infiltration, at a 6-week tumor biopsy. In 10 evaluable patients who completed treatment with TACE/RFA, the ORR was 40% (all PRs). Of evaluable patients with hepatitis C (n = 7), a marked reduction in viral load was noted with the addition of tremelimumab.

This clinical trial, which is being conducted by the National Cancer Institute, remains ongoing. The study hopes to enroll 60 patients (NCT01853618).

Axitinib Plus Chemoembolization Shows High Response

A phase II trial explored the combination of axitinib and TACE in 50 patients with inoperable HCC. In this study, axitinib was administered at 5 mg twice daily followed by TACE at week 5. Two cycles of TACE were administered.

At a median follow-up of 21.6 months, the median overall survival (OS) was 15.9 months (95% CI, 13.7-31.9). The 2-year OS rate was 41.9% and the median time to progression was 10.4 months. In 45 evaluable patients, the ORR was 68.2%, which included complete responses. In all, 6 patients were downstaged and underwent surgical resection. Samples from these resections were analyzed, with 5 showing signs of complete tumor necrosis.

The most frequently observed grade &ge;3 AEs were elevated ALT (40%), hypertension (24%), and hand-foot skin reaction (12%). Development of hypertension during treatment with axitinib was associated with a better OS. In those who developed hypertension, the median OS was 25.0 versus 13.7 months in those who did not develop this AE (

Findings presented at the ASCO meeting represented the final analysis of this study, which was conducted in China (NCT01352728). A second phase II study, in Taiwan, is assessing axitinib as a second-line treatment in HCC (NCT01273662). At this time, it is unclear whether a phase III study is planned.

1. &nbsp;&nbsp;&nbsp; Duffy AG, Ma C, Ulahannan SV, et al. A phase 1/2 study of TRC105 in combination with sorafenib in hepatocellular carcinoma (HCC).

2. &nbsp;&nbsp;&nbsp; Duffy AG, Makarova-Rusher OV, Kerkar SP, et al. A pilot study of tremelimumab  a monoclonal antibody against CTLA-4 &ndash; in combination with either trans catheter arterial chemoembolization (TACE) or radiofrequency ablation (RFA) in patients with hepatocellular carcinoma (HCC).

3. &nbsp;&nbsp;&nbsp; Chan SL, Yeo W, Mo F, et al. A phase II clinical trial on combined axitinib and transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC): Final results and evaluation of clinical predictor for response.

Novel Agents Show Early Promise in HCC

Patients with hepatocellular carcinoma (HCC) that was related to hepatitis B virus (HBV) infection were found to have more advanced clinicopathologic features and worse outcomes compared with those with hepatitis C virus (HCV)-related HCC, according to a retrospective analysis conducted on historical data from patients treated at the MD Anderson Cancer Center.

"Hepatitis B HCC patients tended to have shorter overall survival and time to progression regardless of systemic therapy, although the difference was not statistically significant," Marc Uemura, MD, MBA, fellow, hematology and medical oncology, MD Anderson Cancer Center, said during a presentation of the results at the 2015 ASCO Annual Meeting.

In the study, single institution medical records for 815 patients with viral-related HCC from 1992 to 2011 were reviewed. HCV was present in 472 patients (58%), while HBV was seen in 343 individuals (42%). Viral status was confirmed by serology.

A number of clinical and pathologic differences were seen between the two groups of patients. Those in the HBV versus HCV arm, respectively, were younger (57.4 vs 61.3 years;

<.001), had poorly differentiated tumors (26.5% vs 18.8%;

= .001), a higher incidence of portal thrombosis  (35.7% vs 30.2%;

= .05), larger tumors (>5cm; 49.4% vs 35.2%;

= .02), higher tumor volume (>50%; 42.9% vs 26.6%;

< .001), and lower levels of underlying cirrhosis (59.5% vs 86%;

Other lifestyle factors varied between the two arms. Compared with the HBV group, those with HCV-related HCC had a higher coincidence of smoking (73% vs 56.4%;

<.001), alcohol consumption (70.1% vs 49.3%;

<.001), and type 2 diabetes (23.5% vs 18.3%;

In terms of therapy and biomarker differences, more patients in the HBV arm had received systemic therapy (36.9% vs 27.5%;

<.001); however, more patients with HCV were treated locally (27.5% vs 17.6%;

<.001). AFP levels in the HBV arm were 55,708 IU/mL (&plusmn;10,950) compared with 17,894 IU/mL (&plusmn;4,662) in the HCV arm (

A trend toward better overall survival (OS) was seen in the HCV arm versus HBV; however, this was not statistically significant (

= .9). In the HCV arm, the median OS was 10.9 versus 9.3 months in the HBV arm. Similarities in OS held up across treatment modalities, with a trend favoring improved survival seen in HBV patients treated with ablation (27.3 vs 32.5 months;

"Across all of these categorical groups, the hepatitis B patients tended to do a little worse than the hepatitis C patients in terms of overall survival," Uemura observed.

For time to progression (TTP), sorafenib was the only treatment that led to a significant difference between the two groups. In the HCV arm sorafenib showed a 7.6-month TTP compared with 3.8 months in the HBV arm (

"Our results suggest the need for HCC stratification based on hepatitis status in clinical. However, multi-institutional prospective validation studies are warranted," Uemura concluded.

Uemura MI, Kaseb AO, Abdel-Wahab R, et al. Hepatitis B- and C-associated hepatocellular carcinoma in a large US cancer center: Do clinicopathologic features or patient outcomes differ by the potentially causative viruses? J Clin Oncol. 2015;33 (suppl; abstr 4011).

Patients with hepatocellular carcinoma (HCC) that was related to hepatitis B virus (HBV) infection were found to have more advanced clinicopathologic features and worse outcomes compared with those with hepatitis C virus (HCV)-related HCC.

Hepatitis B Confers Worse Outcomes, More Advanced Disease

Provided by Dr. I-Chen Tsai, Taichung Veterans General Hospital, Taichung, Taiwan.

Although liver transplantation may be a more ideal treatment option compared with resection for many patients with hepatocellular carcinoma (HCC), donor availability remains a major limiting factor to its widespread incorporation. Variations in outcomes between patients treated with resection and transplantation, along with a potential strategy to increase donor availability while maintaining outcomes, were the focus of two recent studies published in the

Journal of the American College of Surgeons

Overall, results from the first study, led by William C. Chapman, MD, indicated that liver transplantation does have an overall and disease-free survival advantage over resection among patients who qualify for both treatment modalities.

However, due to resource limitations, liver resection often remains the recommended therapy for patients with resectable HCC.

A second study, led by Mizuki Ninomiya, MD, PhD, shed light on the potential for living donor liver transplantation (LDLT) to offer an increased source of donors for patients with unresectable HCC.

In their study designed to compare centers utilizing LDLT versus deceased donor liver transplantation (DDLT) as a primary treatment choice, HCC recurrence rates appeared similar regardless of graft source.

These studies help to improve local therapies for patients with HCC, which is increasingly being diagnosed at earlier stages as a result of routine screening in patients with cirrhosis.

Despite more patients being diagnosed at earlier stages, the estimated 5-year survival rate in the United States remains less than 12%, emphasizing the need for improved therapeutic options for patients with HCC.

&ldquo;Liver transplantation and liver resection are the mainstays of surgical therapy for HCC,&rdquo; Chapman, and colleagues noted in their report comparing resection with transplantation.

However, most of the patients presenting with HCC also have associated chronic liver disease,

which may impact their eligibility for these procedures. In fact, only 25% to 40% of US patients undergo some form of curative therapy upon presentation.

Liver resection with partial hepatectomy is currently the standard of care for patients with HCC who have well-compensated cirrhosis and no evidence of portal hypertension.

In the population of patients without chronic liver disease, resection can yield 5-year overall survival rates around 50%.

&ldquo;Liver resection is an attractive therapy because it is immediately available, allows for pathologic assessment of the tumor and background liver, and does not require use of an increasingly scarce donor liver that could be used for the overall transplant pool,&rdquo; the authors added.

In addition, there is evidence to suggest that resection may be more cost-effective than liver transplantation.

Despite these benefits, liver resection is not without its limitations, as 60% to 80% of patients experience intrahepatic recurrences of HCC in the remnant liver by year 10 of follow-up.

Additionally, effective treatment options for post-resection recurrence remain poorly defined. In fact, some reports suggest that patients undergoing salvage transplantation after post-resection recurrence may have worse outcomes versus those undergoing initial liver transplant.

In contrast to liver resection, Chapman and colleagues noted, &ldquo;liver transplantation offers a more ideal treatment for HCC because it achieves removal of the tumor and also the potential sites of recurrence in the diseased liver.&rdquo;

Rates of survival post liver transplantation have greatly improved following incorporation of the Milan criteria, which provides a strict standard for patient selection and limits transplant to those in earlier stages of disease. These criteria exclude liver transplantation in individuals with vascular invasion involving intrahepatic portal or hepatic veins, or those with evidence of metastases.

Unfortunately, &ldquo;given the rigorous selection process and the ever-present scarcity of donor organs,&rdquo; Chapman added, &ldquo;liver transplantation as the treatment of choice for HCC is not feasible in a significant number of patients who present with [the disease].&rdquo;

It is important to note that studies comparing the outcomes of liver resection versus transplantation in patients with HCC are impacted by the fact that patient eligibilityand thus baseline patient characteristics&mdash;often differ between the 2 treatment groups.

&ldquo;Patients with normal background liver (ie, no fibrosis or cirrhosis) almost never undergo transplantation,&rdquo; Chapman and colleagues explained, while &ldquo;those with decompensated cirrhosis and/or portal hypertension almost never undergo hepatic resection.&rdquo;

While the use of liver transplantation is &ldquo;almost never considered in patients with normal background liver,&rdquo; most HCC patients do present with chronic liver disease, which often confounds treatment selection, especially among individuals who qualify for both treatment options.

For the subset of patients with early stage malignancy and well-compensated cirrhosis or hepatic fibrosis, both transplant and resection may be feasible; unfortunately, for these individuals, controversy remains as to which approach is ideal.

One study in 2013 indicated that liver resection yields significantly greater rates of disease recurrence, where the 10-year recurrence risk was 83% following resection versus only 20% following liver transplant.

Ten-year survival rates in this study were also higher for liver transplant compared with resection, at 49% versus 33%, respectively.

Despite these findings, other intention-to-treat analyses have countered that overall survival rates are similar between liver resection and transplantation in this setting.

Data from randomized controlled trials directly comparing the 2 treatment modalities are not available at this time.

To address this residual controversy, Chapman and colleagues completed an extensive retrospective study, gathering data from 5 large US liver centers spanning over 20 years of clinical practice.

The study included patients with HCC who were surgically treated via either liver resection or transplantation between January 1, 1990, and August 31, 2011. &ldquo;We were especially interested in patients with background liver disease who might potentially qualify for either surgical therapy,&rdquo; the authors noted.

&ldquo;Our results suggest that, controlling for patient characteristics that often confound analyses of outcomes from retrospective data, liver transplantation had significantly greater overall and disease-free survivals,&rdquo; concluded Chapman.

This outcome was particularly notable among cirrhotic patients with tumors meeting Milan criteria, &ldquo;who theoretically, would have been candidates for either therapy.&rdquo;

In this patient population, 5- and 10-year overall survival rates were 74.3% and 53.7% for liver transplantation compared with 46.5% and 15.2% for liver resection.

Similar results were obtained for disease-free survival, reaching 71.8% and 53.4% for liver transplant at 5 and 10 years compared with 18.4% and 3.0% for liver resection, respectively. These trends remained unaffected by age or the presence of cirrhosis.

Taken together, the authors concluded that &ldquo;patients with HCC and background liver disease are likely to have better outcomes in short- and long-term follow-up by undergoing liver transplantation, if they qualify.&rdquo;

These findings suggest that ideally, liver transplantation should be encouraged as an initial therapy for HCC in the setting of background liver disease, even among individuals suitable for resection.

Unfortunately, despite poorer treatment outcomes following resection, Chapman and colleagues concluded that, from a &ldquo;resource use standpoint,&rdquo; candidates who qualify for either therapy might still need to be managed via resection rather than transplant.

This recommendation is necessary to &ldquo;lessen the impact of liver transplantation on the overall donor pool,&rdquo; the authors explained, &ldquo;which is already compromised with the ever expanding waiting list of patients needing [transplant] and for whom no other options exist.&rdquo;

They urgently called for additional strategies, such as adjuvant therapy, in an effort to lessen the gap in treatment outcomes between resection and transplant.

Additional strategies are especially important for those who do not qualify for liver transplantation. Based on tumor size and the presence of cirrhosis, only around 10% of patients in the Chapman study who underwent liver resection would have met the criteria for liver transplant.

Increasing Options for Liver Transplantation

Even if recurrence rates following liver resection could be improved, many patients with HCC may have more advanced, unresectable disease. &ldquo;In the United States alone,&rdquo; wrote Ninomiya and colleagues, &ldquo;approximately 7,000 new patients with HCC are put on the waiting list for DDLT each year, and 15% die during the waiting period&hellip;due to the relative shortage of deceased donors.&rdquo;

Due to the extended waiting periods and consequent risk of tumor progression associated with DDLT, Ninomiya and other researchers proposed LDLT as an alternative.

The use of LDLT has the potential to increase the supply of organs available for transplant; however, controversy remains as to whether this approach can maintain overall and disease-free survival rates comparable to those achieved with DDLT.

In the United States, DDLT accounts for the large majority of liver transplantation procedures, especially among patients who meet Milan criteria.

As LDLT is often reserved for those excluded from DDLT, many studies in the United States may be subject to bias. In contrast, many Asian countries resort to LDLT as a primary therapy for patients with unresectable HCC, due to the limited supply of deceased donors.

Taking this into consideration, Ninomiya and colleagues set out to compare outcomes of LDLT versus DDLT in settings where each procedure would be the &ldquo;first treatment choice&rdquo; for patients with unresectable HCC.

In summary, 133 patients receiving LDLT from Kyushu University in Japan were compared with 362 patients receiving DDLT from Mount Sinai Medical Center in New York. The authors specified a primary endpoint of recurrence rate after liver transplantation (LT).

Interestingly, for the primary endpoint of recurrence rate, there was no significant difference between groups over 1, 3, and 5 years of follow-up. This finding led the authors to conclude that &ldquo;LDLT is a viable treatment option for unresectable HCC, providing similar recurrence rates to those achieved with DDLT.&rdquo;

Findings also indicated that the survival rate for patients undergoing LDLT was significantly better compared with those receiving DDLT. However, the authors noted that, due to differing baseline patient characteristics and potential selection bias, &ldquo;the current results do not necessarily represent superiority of LDLT over DDLT in terms of survival benefits.&rdquo;

In lieu of strategies to improve resection outcomes in these cases, and in the face of increasing numbers of patients with unresectable disease, alternatives with the potential to increase donor availability are crucial for optimizing treatment outcomes in this setting.

&ldquo;Given the static supply and the increasing demand for usable organs for transplantation,&rdquo; Chapman and colleagues concluded, &ldquo;there is urgency in exploring methods to increase the supply of organs.&rdquo;

While present findings offer one potential strategy for improving donor availability, additional efforts to expand the donor pool and improve resection outcomes via adjuvant therapies remain critical to the field.

1.  &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Ninomiya M, Shirabe K, Facciuto ME, et al. Comparative study of living and deceased donor liver transplantation as a treatment for hepatocellular carcinoma.

. 2015;220(3):297-304.e3. doi:10.1016/j.jamcollsurg.2014.12.009.

2.  &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Chapman WC, Klintmalm G, Hemming A, et al. Surgical treatment of hepatocellular carcinoma in North America: can hepatic resection still be justified?

. 2015;220(4):628-637. doi:10.1016/j.jamcollsurg.2014.12.030.

3.  &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Cicalese L. Hepatocellular Carcinoma. May 2014. http://emedicine.medscape.com/article/197319-overview. Accessed March 12, 2015.

4.  &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Mittal S, El-Serag HB. Epidemiology of HCC: Consider the Population.

. 2013;47(0):S2-S6. doi:10.1097/MCG.0b013e3182872f29.

5.  &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Simonetti RG, Camm&agrave; C, Fiorello F, Politi F, D&rsquo;Amico G, Pagliaro L. Hepatocellular carcinoma. A worldwide problem and the major risk factors.

6.  &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Llovet JM, Beaugrand M. Hepatocellular carcinoma: present status and future prospects.

. 2003;38:136-149. doi:10.1016/S0168-8278(02)00432-4.

7.  &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Belghiti J, Regimbeau JM, Durand F, et al. Resection of hepatocellular carcinoma: a European experience on 328 cases.

8.  &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Lim KC, Wang VW, Siddiqui FJ, et al. Cost-effectiveness analysis of liver resection versus transplantation for early hepatocellular carcinoma within the Milan criteria.

. 2015;61(1):227-237. doi:10.1002/hep.27135.

9.  &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Adam R, Azoulay D, Castaing D, et al. Liver resection as a bridge to transplantation for hepatocellular carcinoma on cirrhosis: a reasonable strategy?

. 2003;238(4):508-518; discussion 518-519. doi:10.1097/01.sla.0000090449.87109.44.

10.  &nbsp;&nbsp;&nbsp;&nbsp; Sapisochin G, Castells L, Dopazo C, et al. Single HCC in cirrhotic patients: liver resection or liver transplantation? Long-term outcome according to an intention-to-treat basis.

. 2013;20(4):1194-1202. doi:10.1245/s10434-012-2655-1.

11.  &nbsp;&nbsp;&nbsp;&nbsp; Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation.

. 1999;30(6):1434-1440. doi:10.1002/hep.510300629.

12.  &nbsp;&nbsp;&nbsp;&nbsp; Facciuto ME, Rochon C, Pandey M, et al. Surgical dilemma: liver resection or liver transplantation for hepatocellular carcinoma and cirrhosis. Intention-to-treat analysis in patients within and outwith Milan criteria.

. 2009;11(5):398-404. doi:10.1111/j.1477-2574.2009.00073.x.

13.  &nbsp;&nbsp;&nbsp;&nbsp; Fisher RA, Kulik LM, Freise CE, et al. Hepatocellular carcinoma recurrence and death following living and deceased donor liver transplantation.

Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg

. 2007;7(6):1601-1608. doi:10.1111/j.1600-6143.2007.01802.x.

14.  &nbsp;&nbsp;&nbsp;&nbsp; Bhangui P, Vibert E, Majno P, et al. Intention-to-treat analysis of liver transplantation for hepatocellular carcinoma: living versus deceased donor transplantation.

. 2011;53(5):1570-1579. doi:10.1002/hep.24231.

15.  &nbsp;&nbsp;&nbsp;&nbsp; Hwang S, Lee S-G, Belghiti J. Liver transplantation for HCC: its role: Eastern and Western perspectives.

. 2010;17(4):443-448. doi:10.1007/s00534-009-0241-0.

Although liver transplantation may be a more ideal treatment option compared with resection for many patients with hepatocellular carcinoma (HCC), donor availability remains a major limiting factor to its widespread incorporation.

Transplant Versus Resection for Hepatocellular Carcinoma

Controversy over optimal surveillance methods for hepatocellular carcinoma (HCC) continues to drive ongoing investigation into improved biomarkers and imaging techniques. Recent screening studies have focused on the utilization of alpha-fetoprotein (AFP) with ultrasound and abbreviated MRI approaches.

demonstrated that AFP may be a helpful complement to traditional ultrasound-based surveillance programs, one that is particularly useful among patients with viral-induced cirrhosis.

Additionally, MRI and CT are occasionally employed as a means of increasing HCC detection sensitivity among high-risk patients in place of conventional ultrasound. According to one recent study, per-patient sensitivities for HCC detection were 64%, 76%, and 85%, for ultrasound, CT, and MRI, respectively.

Although alternative imaging techniques offer the potential for improved sensitivity, limiting factors often prevent their widespread use as an HCC surveillance tool. For instance, &ldquo;despite higher diagnostic accuracy than ultrasound and CT,&rdquo; explained Robert M. Marks, MD, from the Naval Medical Center San Diego, &ldquo;the greater expense, long examination times, and relatively limited availability remain a challenge to using MRI in HCC surveillance.&rdquo;

Due to the factors limiting CT and MRI approaches, &ldquo;their roles as surveillance tools for detecting early-stage HCC in patients with cirrhosis remains uncertain,&rdquo; noted Te-Sheng Chang, MD, PhD, and colleagues in their recent report on the addition of AFP.

The use of MRI, for instance, may be better suited to confirming positive surveillance results, rather than screening for HCC initially.

In answer to these limitations, a recent study by Marks and colleagues in the

attempted to model an abbreviated MRI examination protocol and assess its potential as an HCC surveillance tool.

With a gadoxetic acid-enhanced hepatobiliary phase and T2-weighted single-shot fast spinning echo (SSFSE), the abbreviated protocol was able to maintain the high per-patient sensitivity and negative predictive value of the MRI technique, while minimizing logistic limitations, such as cost and procedure time.

&ldquo;We found that per-patient sensitivity for the detection of HCC with an abbreviated MRI examination was similar to the reported sensitivity for the complete study with gadoxetic acid,&rdquo; wrote the authors.

According to their findings, the abbreviated protocol reached 82.6% sensitivity, which is not only comparable to the complete MRI, but also considerably greater than that reported in the literature for ultrasound-based surveillance.

Resources such as the abbreviated MRI procedure may be useful for improving surveillance sensitivity and identifying patients requiring follow-up with more costly and time-intensive imaging techniques. With the potential to reduce the current 2040 minute procedure time to a 15-minute time slot and 5-minute scan, the authors estimated that switching from a complete MRI to an abbreviated MRI surveillance program may afford a total cost savings of nearly 31%.

Overall, the study by Marks and colleagues concluded that the abbreviated MRI technique may be beneficial for centers currently utilizing full-length MRI for HCC surveillance.

The authors went on to stress that additional studies are still necessary to determine the relative cost-to-benefit ratio of utilizing this technique compared with the conventional ultrasound approach.

Role of Biomarkers for Improving Ultrasound Sensitivity

Until alternative surveillance modalities, such as the abbreviated MRI, are thoroughly validated and widely available, methods for improving ultrasound sensitivity are of critical importance. In the absence of alternative modalities, several groups have investigated the utility of serum biomarkers, such as AFP, as potential surveillance tools. By itself, however, AFP has proven suboptimal in detecting HCC.

&ldquo;There have been false-positive results, as elevated AFP also occurs in chronic liver disease and other malignancies,&rdquo; explained Chang and colleagues in their recent report.

False-negative results may also occur when using this biomarker, as not all HCCs secrete AFP. &ldquo;This is particularly veritable for early-stage HCCs, which are the targets of surveillance,&rdquo; added the authors.

Due to these potential limitations, the American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of the Liver (EASL) recently discouraged the use of AFP as a surveillance modality for HCC.

Despite this, interest remains as to whether the biomarker may still provide some benefit when used as a complement to conventional ultrasound.

As ultrasound is a subjective, highly operator-dependent technique, Chang explained that &ldquo;the detection of increased AFP levels during surveillance may alert the surveyor and thus trigger a more intense survey.&rdquo;

In light of the controversy over the benefits of AFP in HCC surveillance, the performance of these modalities in a real-world practice setting was examined through the comparison of ultrasound-based surveillance or AFP measurement alone versus a combined approach.

Investigators retrospectively evaluated patients with cirrhosis who were screened for HCC at a tertiary referral hospital in Southern Taiwan between January 2002 and July 2010. The median duration of follow-up in the study was 4.75 years.

Of the 1597 patients analyzed over the follow-up period, 22.7% developed HCC. With a cutoff value of 20 ng/mL, the use of AFP measurement alone resulted in a sensitivity of 52.9% and a specificity of 93.3%. Comparatively, the sensitivity and specificity of ultrasound surveillance was 92.0% and 74.2%, respectively.

Interestingly, investigators found that by combining ultrasound and AFP, the sensitivity of ultrasound alone was significantly improved from 92.0% to 99.2%. Unfortunately, specificity was simultaneously lowered from 74.2% to 68.3%.

Further investigation demonstrated, however, that requiring an increase in AFP levels greater than twice the nadir during the previous year in addition to the 20 ng/mL threshold was able to increase the specificity of combined ultrasound and AFP surveillance from 68.3% to 71.5%. In addition, the improved sensitivity of 99.2% was maintained.

&ldquo;Our results support the concept that an increased AFP level is a risk factor for HCC development,&rdquo; Chang and colleagues wrote. Moreover, compared with individuals who did not develop HCC, patients developing the disease exhibited greater AFP levels within the 12 months leading up to HCC onset.

These findings were similar to results published in

Cancer Epidemiology, Biomarkers, and Prevention

by Amit G. Singal, MD, and colleagues from the University of Michigan, in May 2012. This study demonstrated a significantly increased HCC surveillance sensitivity when combining ultrasound and AFP in a real-world clinical setting, with a minimal loss of specificity versus ultrasound alone.

The improved sensitivity of combined ultrasound and AFP versus ultrasound alone remained significant in the subsets of patients with hepatitis B (HBV) or hepatitis C virus (HCV) infection, as well as in HBV and HCV co-infected individuals.

In contrast, the finding did not hold true for cirrhotic patients who were negative for both HBV and HCV.

Investigators concluded that the benefits of combined ultrasound and AFP screening were not as marked in patients with nonviral cirrhosis.

As most of these patients had alcohol-induced cirrhosis, the authors concluded that &ldquo;AFP measurement is not as effective as a complementary method to ultrasound for HCC surveillance in western countries, where most liver cirrhosis is related to alcoholism.&rdquo;

Despite the AASLD and EASL guidance that AFP should not be used as a surveillance modality, the findings of Chang and colleagues illustrate that use of this biomarker may still be relevant as a complement to ultrasound.

The combined approach may be able to increase surveillance sensitivity and improve HCC detection in patients with cirrhosis, particularly among those with hepatitis-driven disease.

&ldquo;Despite considerable efforts in developing new serum biomarkers for detecting or diagnosing HCC,&rdquo; noted Chang, &ldquo;none have been proven superior to AFP.&rdquo;

As such, the authors concluded that &ldquo;until a superior alternative biomarker is developed, AFP measurement should be used in combination with ultrasound for HCC surveillance&hellip;[especially in] those with viral hepatitis-induced cirrhosis.&rdquo;

HCC is the most common form of cancer affecting the liver, driven mainly by viral hepatitis infection or alcohol-induced cirrhosis. This malignancy is the third leading cause of cancer deaths worldwide, with over 500,000 individuals currently affected.

Predicted to be a major health concern in future decades, data from the Surveillance Epidemiology and End Results (SEER) program indicate that HCC is the fastest growing cause of cancer mortality in the United States.

In fact, disease incidence has more than doubled over the last two decades, with a near 2-fold increase in the HCC mortality rate over the last 5 years alone.

Patients diagnosed at advanced stages are often precluded from potentially curative treatment options such as surgical resection or liver transplantation, making early detection a priority for improved prognosis.

Due to the benefits of early detection on patient survival,

the AASLD and the EASL currently encourage HCC surveillance as a measure to promote early detection in high-risk patients with chronic liver disease.

As a low cost and readily accessible technique, most organizations recommend the use of ultrasound for HCC surveillance. Unfortunately, per-patient sensitivity is reportedly insufficient with this method, falling below 65% when detecting small or early-stage HCCs.

As a result, the search for alternative methods to improve HCC surveillance is an important area of ongoing research.

1.  &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Chang T-S, Wu Y-C, Tung S-Y, et al. Alpha-Fetoprotein Measurement Benefits Hepatocellular Carcinoma Surveillance in Patients with Cirrhosis.

. 2015;110(6):836-844. doi:10.1038/ajg.2015.100.

2.  &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Yu NC, Chaudhari V, Raman SS, et al. CT and MRI improve detection of hepatocellular carcinoma, compared with ultrasound alone, in patients with cirrhosis.

Controversy over optimal surveillance methods for hepatocellular carcinoma (HCC) continues to drive ongoing investigation into improved biomarkers and imaging techniques. 

July 2015 | HCC Monitor

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