Should patients with unresectable HCC undergo systemic therapy?

Click here to read the Cover Story, “Obesity, hepatitis C epidemics drive ‘alarming’ increase in liver cancer incidence, mortality.”

Yes.

The appropriate and right choice for patients with metastatic disease is systemic therapy, not locoregional therapy.

Treating with local therapy addresses a problem at the treatment location only, whereas systemic therapy would address metastatic disease wherever it is, wherever it might be and wherever it might go.

This question remains relevant because the systemic therapy approach took a long time to evolve to where it is today for liver cancer with available standards of care (eg, sorafenib and regorafenib), whereas the effort for local therapy evolved earlier. This helped understand the local therapy approach as a potential choice, despite its limitations for metastatic disease.

Historical standard-of-care local therapies include embolization or chemoembolization. Other developments followed, the latest of which was yttrium-90 resin microspheres that can attack the cancer in the liver. It’s important to note that yttrium-90 did not show a survival benefit compared with sorafenib.

A limitation of applying local therapy for metastatic disease is best exemplified by a study that evaluated embolizing a small lesion on the left side of a mouse’s liver, which had cancer on the right side of the liver. Results showed the tumor on the right side grows, potentially worsening the disease with local therapy. A doctor who tells a patient not to worry about disease outside the liver — such as small lung lesions — can be at fault, because all lesions can potentially be problematic.

I heard of a patient who had a very small lesion in the vertebral body, that was ignored because it was considered to not be of any immediate concern. The patient went for chemoembolization for the liver lesion, and the tumor in the spine grew enough that it caused the patient to get a cord compression. Systemic therapy is for systemic disease and local therapy should be limited to local disease.

So where do we go from here? Rather than debating between treatment options, we should be more thoughtful of how — and if — we can combine the two. Three large clinical trials have combined chemoembolization and sorafenib. They were negative, but it does not mean the concept is truly negative.

At Memorial Sloan Kettering Cancer Center, we are studying the combination of chemoembolization with immunotherapy. This may not necessarily replace local therapy, but systemic therapy after local therapy may very well play a role in the future of local disease.

Reference:

Vilgrain V, et al. Abstract GS-012. Presented at: The International Liver Congress; April 19-24, 2017; Amsterdam.

Ghassan Abou-Alfa, MD, MBA, is a medical oncologist at Memorial Sloan Kettering Cancer Center. He can be reached at abou-alg@mskcc.org. Disclosure: Abou-Alfa reports consultant roles with or research funding from Agios, Amgen, Aptus, Array, Aslan, Astellas, AstraZeneca, Bayer, Boston Scientific, Bristol-Myers Squibb, CARsgen, Casi, Celgene, CytomX, Daiichi Sankyo, Debiopharm Group, Delcath, Eli Lilly, Exelixis, Genentech, Gilead, Halozyme, Incyte, Inovio Pharmaceuticals, Ipsen, MabVax Therapeutics, Merck, MedImmune, Momenta, OncoMed Pharmaceuticals, Onxeo, PCI Biotech, Roche, Sanofi, Servier, Silenseed, Sillajen, Sirtex and Yakult.

No.

Locoregional therapy historically has been used as the standard of care for the treatment of HCC. Locoregional therapy consists of several variations. These include direct transarterial infusion of chemotherapy, direct transarterial infusion of chemotherapy combined with embolization procedures — such as blocking the tumors — and various therapies that are tumor directed, such as alcohol injection, radiofrequency ablation and microwave ablation, a newer approach.

It is well established that these therapies — alone or in combination — are known to produce local effect and possibly regional effect. Most of these therapies are, for lack of a better word, palliative therapies, because they are standard of care for resectable HCCs — either resection or liver transplantation, depending on the criteria that the tumor can meet. If the tumor meets transplant criteria, then transplant is, by far, the best option. For unresectable and untransplantable tumors, the therapy is, by definition, a palliative therapy because it cannot cure a patient. To accomplish a sustainable, meaningful effect on the tumor, no systemic chemotherapy has ever shown to be consistently effective.

The advantage of systemic chemotherapy is that it is less risky, less toxic, has fewer side effects and carries less risk for major complications than locoregional therapies. Embolization can cause hepatic necrosis and other additional problems related to arteries, such as arterial dissection. Regional therapies — like radiofrequency ablation, alcohol injection and microwave ablation — can sometimes cause liver abscess, which requires significant treatment and can be lethal.

Everything is a tradeoff, but locoregional therapies clearly produce a measurable effect measured in tumor necrosis, tumor shrinkage and, in certain cases, complete destruction of the actual lesion. This, in my opinion, gives better patient survival than systemic chemotherapy, including the most well-known systemic chemotherapy, sorafenib.

Dmitri Alden, MD, FACS, is a surgical oncologist at Lenox Hill Hospital. He can be reached at dalden@aldensurgery.com. Disclosure: Alden reports no relevant financial disclosures.