Richard S. Finn, MD and a group of peers discusses that case of a 77-year-old woman who presented to her primary care physician complaining of abdominal pain and fatigue.
During a Targeted Oncology Case-Based Roundtable event, Richard S. Finn, MD, professor of Medicine, Division of Hematology/Oncology, director, Signal Transduction and Therapeutics Program at UCLA Jonsson Comprehensive Cancer Center David Geffen School of Medicine at UCLA in Los Angeles, CA, discussed the case of a 77-year-old woman with hepatocellular carcinoma.
FINN: You say no on biopsy, which I would agree with because this patient has cirrhosis and a LR5 lesion.
If someone is not cirrhotic, you can’t use the LI-RADS classification. In addition, AFP—though elevated and concerning—is not the basis for the diagnosis of liver cancer. It’s imaging that drives that.
What if the patient didn’t have cirrhosis? Would you have recommended a biopsy?
KOSIEROWSKI: Yes, I would biopsy.
SAAB: If she has fatty liver [and] if we were convinced [the disease was] noncirrhotic, I may biopsy. But with the AFP that high, unless the patient had vesicular cancer, I’m not sure what would cause AFP that high.
FINN: Unlikely in a woman—other germ cell tumors. Part of the issue is that some cholangiocarcinomas can also express AFP. It’s not so specific. What if it was an LR4 lesion? LR4 is still 60% to 70% likely to be liver cancer. Let’s say we have the same patient with cirrhotic LR4; would you recommend a biopsy then?
BEJJANI: Yes, I would. There’s still 30% to 40% of patients that [do not have HCC if LR4 is] about 60% to 70%. There could still be other things. If [there] was [a] possibility of it being a mixed HCC and cholangiocarcinoma, that would be important to know for treatment purposes.
FINN: There’s nothing to suggest that, but the guidelines would say that one option would be to do an MRI. This patient had a CT scan. If you did not want to do an invasive modality, you could do an MRI. Maybe on that modality, it would be LR4. It wouldn’t meet all the criteria.
This is a larger lesion, it’s 4.5 cm. We [often] see a 1.5-cm lesion, which is LR4, and at that point there’s no rush to make the diagnosis, given it’s so small. Maybe repeating [scans] in a few weeks would be reasonable.
For my oncology colleagues, many of us are [now] trained to get next-generation sequencing [NGS]. Assuming this patient had a biopsy [and] HCC, would you recommend any further genetic testing on this tumor?
GOWDA: Is there an absolute level of AFP by itself where you would not recommend a biopsy? It used to be 400 ng/mL or higher.
FINN: AFP has come off any guideline for diagnosis for liver cancer. I’ll share a quick case. There’s a patient I saw a few months ago; he was 45 years old with hepatitis C and some cirrhosis. He came to me and one of our surgeons for a second opinion for a large tumor in his liver. He had a biopsy that labeled it liver cancer and his AFP was 25,000 ng/mL. He had been started on treatment, and I concurred and didn’t have anything else to say.
[However], my surgical colleague had the biopsy reviewed at UCLA, and the report said that it couldn’t rule out germ cell tumor. I [told the] patient, “We could repeat the biopsy if you want. It is 90% likely this is liver cancer, but it would make a big difference for you.” As it turns out, he had a germ cell tumor and got platinum therapy, ifosfamide [Ifex], and etoposide. He had a significant response and he’s going to [have] surgery to remove the residual tumor.
GOWDA: Was the liver cirrhotic?
FINN: He had some cirrhotic changes on his scan. This patient had a biopsy. The imaging wasn’t enhancing what we look for in imaging. An enhancing tumor with washout made it difficult to read, but the surgeon picked it up on it and had the pathologist review.
Would you send [our patient’s tissue] for NGS testing or any other genetic testing specifically?
KOSIEROWSKI: If it was a liver tumor, I would not. However, with the lung lesion there, I might consider it. I want to make sure that we don’t have coprimaries if there’s something on the chest x-ray in the past.
FINN: A 4.5-cm [lesion, and] to have all these lung metastases, is unusual. That’s not unreasonable to confirm metastatic disease for someone who had a resection and then has the first recurrence of metastatic disease. I often biopsy it. But it doesn’t sound like anyone is suggesting, say, that we would do NGS; typically, that is not done because there are no targets that are validated in liver cancer. You’re alluding to whether you find ALK or EGFR mutations in the lung. Short of NTRK mutations, which are somewhat agnostic, those are rare.
SHAHIDI: What if you did NGS and it showed an IDH mutation that occurs in cholangiocarcinoma? What do you do then?
FINN: I would probably save it for later. Even in cholangiocarcinoma, that’s a second-line decision point, but some liver cancers have a mixed cell of origin. I don’t know if that’s not an impossible scenario.
Is there any further imaging? Would anyone get a bone scan?
BEJJANI: I wouldn’t get a bone scan unless they’re symptomatic.
CHOI: Normally we don’t unless they’re a transplant candidate, and this patient is not.
FINN: Two-thirds of you would recommend atezolizumab [Tecentriq] and bevacizumab [Avastin]. A quarter would say lenvatinib [Lenvima], and there was 1 vote for the other. Does anyone want to offer the “other” option?
FANG: I voted for “other.” I think this patient can be treated with radioembolization therapy, like Yttrium-90 [Y90].
FINN: The clarifying thing here is this patient has a metastatic disease to the lungs. In that setting, the role of local treatment is not well defined.
FANG: We have an aggressive interventional radiologist; he treats every patient. I feel that for this patient with disease in the liver, local therapy first may have some potential benefit.
FINN: That’s interesting…an aggressive interventional radiologist. If we’re looking at evidence-driven decisions, it’s going to be systemic treatment because these are what have been shown to improve survival.
Does doing local treatment add anything? If anything, there have been studies that have looked at sorafenib [Nexavar] and Y90—2 of them. They looked at sorafenib and Y90 vs sorafenib alone and both of those were negative studies. You’re doing a procedure for no clear benefit, and especially now that we have drugs that are much more active, that approach should go by the wayside.
FANG: Let’s say this patient has a regular response. Say the lung lesion disappears with atezolizumab and bevacizumab. Would you still do local therapy later on a local lesion in the liver?
FINN: This is uncharted territory now because atezolizumab/bevacizumab is relatively new. The response rate is about 30%. That includes 8% complete responses. How long do we keep patients on these drugs?
It’s not known. If we had a patient who’s been on for 2 years who has nothing more in the chest and now has a small 2-[cm] or 3-cm spot in the liver, could you offer that patient an ablation, then give them a break from systemic treatment?
You can, but it’s not clear how long we continue these drugs. Clinical studies of atezolizumab/bevacizumab or nivolumab [Opdivo] were always done to disease progression. The pembrolizumab [Keytruda] studies were geared differently; patients received 36 cycles of the drug and then it was stopped.
GOWDA: The fact that this patient has varices, would that make you do an endoscopy on this patient, see how the varices look, and do some preventive measures, if you used bevacizumab?
FINN: Yes. The studies with atezolizumab/bevacizumab, because of this concern about bleeding with bevacizumab, all required an endoscopy within 6 months of coming on the study, and I think that should be done in practice. Now, if it’s 7 months or 8 months, I don’t think you need to be so exact. But many times, we do imaging on patients with liver disease, and we see that the CT scan picks up varices, and if they haven’t had an endoscopy ever, then they should.
SAAB: For anyone who has cirrhosis, the standard of care is a baseline endoscopy. Depending on what is found, you might intervene with band ligation or β blockers or simply follow the patient. That’s the standard of care.
CHOI: If it’s compensated, it’s every 3 years. If they’re decompensated, it should be annual.
FINN: It’s interesting. A gastrointestinal [GI] doctor called me today about a patient I saw recently who progressed. He had locoregional treatment, developed lung metastases, and we talked about atezolizumab/bevacizumab.
I sent him to see his local endoscopist down in Orange County, and the endoscopist said, “He has large varices in the esophagus and gastric varices.” I asked if he banded them, and he said that he started him on a β blocker. He then suggested that the patient see someone at UCLA. I guess just being large doesn’t mean patients need to get banded. Is that right?
SAAB: That’s correct. They have the option of banding or β blockers. A complex case like the patient you’re talking about with gastric varices—if he didn’t have any gastric varices, it would be easy for banding. For the gastric varices, I don’t know what the consensus is. Even people at UCLA are reluctant to band esophageal varices if there are large gastric varices present.
CHOI: There are 4 types of gastric varices. The most common one is junctional varix, and those you can treat like esophageal varix. Those are bandable, but the other types you cannot band. I don’t know what type of gastric varices this patient had.
FINN: Liver cancer is a multidisciplinary disease, and [that’s a challenge] for the community because it’s a little more siloed. Your interventional radiology, GI, and hepatology people are siloed, and having people interact closely will provide the best care.
FINN: Does anyone here consider age or gender for this patient as being important? She’s a 77-year-old woman.
KOSIEROWSKI: Usually age is not a consideration, but age made me [think about] a TKI [tyrosine kinase inhibitor] in this patient. If she was 67 years old, maybe she could get bevacizumab, but [being] 77 [years old] makes age a factor. Ischemia and bleeding [are also a concern].
FINN: Safety in older patients can be an issue. Those of us that were around when bevacizumab was first approved [saw some concerning adverse events], but overall, we’re convinced it is a safe drug.
What about her etiology of cirrhosis? Her cirrhosis was due to alcohol. Do you think about that differently from someone who had hepatitis B or [hepatitis] C or fatty liver disease in choosing your frontline treatment?
KOSIEROWSKI: I’ve never seen a breakdown of checkpoint inhibitors in alcoholic cirrhosis, and I wonder if it is different. I can see it in viral etiologies.
GOLDBERG: A lot depends on whether she’s still an alcoholic with compliance and everything. If she’s still drinking a lot, that would make a difference. Also, looking at the patient is probably more important than age.
SAAB: Are there data on fatty liver having differential response with some of these agents?
FINN: Studies never stratify by etiology because etiology has never been associated with a differential effect. There was a story [where] sorafenib [initially] worked better in [patients with] hepatitis C than hepatitis B. It has never been borne out in prospective studies. It was also retrospective, and that’s where these data come from.
There was a recent paper in Nature that looked at this question in a metanalysis.1 If you look at those forest plots for end points for overall survival [OS], they break them down from hepatitis B, hepatitis C, and nonviral. Nonviral is alcohol, but it’s also fatty liver hemochromatosis and other things. The patients with nonviral etiology never seem to get as much of a benefit as you see with the [patients with] hepatitis B and hepatitis C. But again, that has not been borne out in a prospective study to answer that question.
The other thing that’s interesting is if you look at response rates, they tend to be the same for nonviral as for viral etiologies. It suggests that maybe there’s some confounding factor that affects the OS readout, and part of this Nature paper was a nice translational component that suggested that, in fatty liver disease, the immune system is not as active, and that’s an explanation for this less benefit. But it’s yet to be borne out.
This patient had Crohn disease and autoimmune disease. Does that play a role in your decision-making of frontline treatment?
CHOI: That would make me hesitant about the atezolizumab, given the autoimmune disease.
FINN: I agree. That’s one of the pretty strong relative contraindications to immunotherapy. She’s on infliximab, which is already an immunosuppressant.
If this patient had a liver transplant 6 years ago and now presents with a new liver lesion and disease in the chest, and we biopsy her liver cancer, will that affect your choice?
FINN: Right, and for the same reason. You’re afraid of rejection as well as the bleeding risk, and that is not a first-line decision to give them immunotherapy. Are there similar concerns about bleeding with the VEGF TKIs?
GOLDBERG: I haven’t had a patient with VEGF TKI who bled a lot, but I remember a couple of patients with bevacizumab who bled.
FINN: That’s fair. There is some class effect. The bleeding has not stood out as much with the TKI.
SAAB: Do we know what they bleed from?
FINN: The most common bleeding is epistaxis. [Usually] low-grade bleeding is not as serious. In the data from atezolizumab/bevacizumab, the patients that had high-risk bleeding events—even though they all had endoscopies—the ones with high-[risk] bleeding events all had main portal vein invasion.2 Not only vascular invasion within the liver but [also] in the main portal vein. It’s not hard to see how that is, given that they probably have more portal hypertension, but they still got a benefit from treatment.
SAAB: Do they bleed from varices, or do they bleed from gastropathy?
FINN: The data are captured as upper GI bleeding or variceal bleeding. It’s not the cleanest answer because it all gets coded into a database, but [most of] them are upper GI bleeding and varices. I mean, they’re single-digit events. We’re not talking about a lot of events to start with.
SAAB: If we had a cirrhotic patient who had varices, if we band them, that patient will be clear for immunotherapies?
FINN: Presumably it’s atezolizumab/bevacizumab. They go together. If they’ve been managed and their bleeding risk is presumed decreased, then I would consider it, depending on their tumor burden.
Does HIV [human immunodeficiency virus] status ever affect your decision?
BEJJANI: Not unless they were poorly controlled. If they have well-controlled HIV, I consider them the same as other patients.
FINN: HIV is a manageable illness. Even if they’re not included in clinical trials, it can be difficult to see why it would behave differently. Performance status or symptom burden—how does that come into play? Does that affect your choice?
BEJJANI: I find atezolizumab/bevacizumab to be more tolerable [regarding] day-to-day [symptoms] like fatigue, diarrhea, and hand-foot-[and mouth disease]. It’s far fewer things to compound their overall experience. If they were more symptomatic or had poor performance status, I may lean toward atezolizumab/bevacizumab.
FINN: There are plenty of patients that have lung cancer, [ECOG] performance status of 2, and are still Child-Pugh A. Conceivably, it’s possible, but I think the Child-Pugh [score] does influence [treatment].
What about the possibility of downstaging a patient? You have a patient who has a large tumor, and you’re hoping to get them to surgery. Does that weigh on your choice of systemic treatment?
KOSIEROWSKI: Not at 77 [years old]. If they were younger, such as 57 [years old], that would be different.
FINN: You’d want something that induces a high response.
WATSON: I think overall response rates are better with the atezolizumab/bevacizumab in comparison with a lot of the other [possible] first-line agents. I’m not sure that I’m looking so much at the possibility of downstaging, but at least in obtaining better response rates, I would favor the atezolizumab/bevacizumab.
FINN: It’s a new age where we have drugs that induce responses. We didn’t have that before, and we have the drugs that induce objective responses. I suspect it’s going to come up…this idea of neoadjuvant systemic treatment. It’s not unusual for patients who have larger primary tumors in the breast, for example, to get neoadjuvant treatment and induce a response, then go to surgery.
Now, obviously this patient is not going to be resectable because she has portal hypertension and she’s sick, but maybe moving ahead for the patient who is borderline resectable—I think there’s a bias for doing locoregional treatment for them.
FANG: Even if it’s a good response in the lung, a surgeon [wouldn’t] consider her to be resectable or transplantable, even if she’s younger, right?
FINN: No, but maybe something locoregional.
Do patient preference and convenience weigh in on your front-line treatment choice?
CHEN: Yes. I think some patients cannot make it and come to intravenous [IV] therapy, so they would prefer oral.
GOLDBERG: Some patients can’t afford TKIs and prefer IV because of reimbursement.
FANG: It’s important to see whether you feel the patient will be adherent. That’s another issue to consider. Whenever you prescribe a pill, there’s always a question about adherence.
FINN: The point is well taken about the potential convenience of oral pills vs coming in for IV therapy, but at the same time—even with these drugs—they still need to be seen proactively to manage their disease.
1. Pfister D, Núñez NG, Pinyol R, et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature. 2021;592(7854):450-456. doi:10.1038/ s41586-021-03362-0
2. Finn RS, Qin S, Ikeda M, et al; IMbrave150 Investigators. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894-1905. doi:10.1056/NEJMoa1915745