Cancer information Cancer treatment

Cancer and Hepatocellular Carcinoma

This is an interesting paper that just came out a few months ago in Hepatology, where the authors looked at a comparison between transplant and surgical resection, based on cost-effective analysis. This was based on life expectancy and not quality-adjusted life years. And the authors pointed out that if you accepted a cost per life year increase between $34,000 and $184,000, which seems a bit high, but accepting perhaps a value under $100,000 here at six months, then any patient who cannot reasonably be transplanted within six months of discovery of their tumor probably, from a cost-effective basis at least, would be a better candidate for surgical resection. Of course studies like this have a great number of assumptions. This is an interesting paper but I’m not sure we can draw too many fast conclusions from it.

Liver cancer. Hepatocellular Carcinoma

Whether or not adjuvant treatment protocols are going to improve the outcome from these trials, I think remains to be seen. Again, I think that if you don’t have a surgeon who understands the scheme of the segmental anatomy of the liver, then these operations are going to be fraught with a great deal of risk. But as every surgeon knows, that even if you restrict these resections to patients with child’s A cirrhosis, many of these patients very quickly act like child’s B or child’s C cirrhotics after they’ve had part of their liver wiped out. So the Spanish group proposed a couple of years ago that there were two variables that really were important in trying to determine which of these patients would deteriorate after surgical resection and which wouldn’t, and they settled on the fact that the bilirubin needed to be normal and that these patients should have hepatic venography done and they should have the absence of portal hypertension. These are perhaps the true indicators of how a patient may do. Concrete indicators rather than simply flying by the seat of ones pants. Finally, the thing that comes over and over on resection is that if the tumor size is greater than 4-5 centimeters in size, the one to two year recurrence rate is going to be prohibitive. So these patients have to have limited disease, to the best of your ability to determine them.
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Percutaneous ethanol injection, on the other hand, can be considered for patients with worse liver function but still the tumor size has to be limited and it usually is ineffective in patients with tumors larger than 5 centimeters in size but can be considered for patients with multiple lesions, 3 centimeters in size or less. The treatment has to be thorough, and this should be in quotation marks because it’s difficult to determine what thoroughness is in this case. The Spaniards not only used loss of enhancement on contrast CT but actually will vigorously biopsy these patients after several sessions of alcohol injection to try to determine if viable tissue remains. We don’t do that. We do use rapid contrast CT scan at our institution and as long as there is evidence of a bit of rim enhancement or a bit of enhancement at the edge of the tumor, then our radiologists will continue to aggressively inject these tumors until that enhancement it lost. I think we’ve had reasonably good results in using that as a gauge for how much longer to continue.
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But point of fact, in patients with isolated lesions smaller than 5 centimeters in size, the Castell’s paper from four or five years ago showed that patients who are thoroughly treated with alcohol injection do about as well as patients with surgical resection. This shows the recurrence rates, one group compared to another, and you will note that it is discouragingly high in both groups within 24 months of treatment, but there is no significant difference between the two and certainly after 36 months there is no significant difference. Both plats level out. Again, not unexpectedly, the survival rates of these patients is also somewhat poor but alcohol injection in these carefully selected patients tends to work about as well as surgical resection. So I think that even here, the case for surgical resection tends to become weaker and, as some authors have pointed out, those patients who tend to be good candidates for surgical resection are probably good candidates for orthotopic liver transplantation also. Certainly in our institution there is more of a trend in that direction.

Liver cancer information

This slide, I think, depicts why we have a bias and that is because we think we are accomplishing something with preoperative chemo-embolization and when we look at the alpha-fetoprotein levels, when Denise looked at the alpha-fetoprotein levels on patients pretreatment, following chemo-embolization at the time of OLT ( orthotopic liver transplant), there was a fairly dramatic drop in the alpha-fetoprotein indicating that chemo-embolization was certainly accomplishing something in these patients and in six months after OLT remained quite low.

Let’s look then at transarterial embolization, or chemo-embolization, not necessarily in a setting of patients who are transplant candidates. This very important paper from Spain came out last year in Hepatology, where they looked at the probability of progression of the initial presenting tumor in patients who were treated with transarterial embolization without chemotherapy added. As you can see, the probability that the tumor would progress over a very short time was really quite high in both groups and there was no significant difference in either group, either embolized or the group that were treated “symptomatically”. As you might expect, the survival curves also fail to show an advantage from transarterial embolization. This nice paper from the French group several years ago in Hepatology had looked at the effect of chemo-embolization, first as a control group and actually suggested that the group who were chemo-embolized did worse than the patients who were treated symptomatically, although the differences were not significant. So I think there has now developed over the last decade or so a general feeling that embolization, whether or not it’s accompanied by chemotherapy, is not a particularly effective way to treat hepatocellular carcinoma. Several papers, including this paper, showed a fairly significant anti-tumoral effect from the treatment but it does not affect survival in these patients. So even though we are somewhat excited about the use of this modality in patients who are waiting on the liver transplant list, there seems to be little reason for enthusiasm in patients who are otherwise untreatable. I would furthermore point out that there is no significant difference between us in studies that are shown in comparison between chemo-embolization and simply arterial embolization. Head-to-head, there is no advantage, one over the other.
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Let’s talk now about surgical resection. Surgical resection continues to come up I think, not only with regard to those patients who don’t have cirrhosis and therefore can undergo segmental or subsegmental resection, but also in regions of this country where waiting lists for liver transplantation may exceed two years. Fortunately United Network of Organ Sharing has made it possible for patients with hepatocellular carcinoma to be listed as a status II-b, which brings some of them into the operating room sooner than they might have otherwise been able to be operated on, but we are still concerned about these long waits until some groups continue to consider patients with reasonably well-maintained liver function for resection. It requires, certainly, a good knowledge of subsegmental anatomy and I think that one of the reasons that we’ve progressed in our ability to operate on these patients is our modern hepatobiliary surgeons have a very good knowledge of subsegmental anatomy and the use of inflow or vascular occlusion in a relatively dry field.

Liver Cancer and Hepatocellular Carcinoma

When one of our liver fellows several years ago first pulled out our data from the early days of our transplant program, looking at patients who were transplanted for hepatoma in various stages, he discovered that this group who presented with a rising alpha-fetoprotein - and this was not a level necessarily associated with the lower values one might see with an active hepatitis C - these were patients who had significant values. Frequently over 400 nanograms per milliliter. When we looked at the survival on these patients, as you might expect, it was really quite good. In other words, we got these patients before the tumor became large or had a chance to progress. But when you looked at the data on any patient who had an identifiable mass lesion prior to transplantation, whether that was even a stage I or II-a patient, then the disease-free survival failed to a disappointing 50% at two years. So I think that hepatologists in our transplant clinic at that point felt that they had to drop back to the drawing board, and try to figure out how we can improve our selectivity on these patients because it seemed that probably most of these patients did poorly because they were simply inadequately staged. There was multicentric disease probably present at the time of transplant that simply had not been identified.
Cancer information
Of course this paper that came out in the New England Journal a couple of years ago was very encouraging for all of us, and showed that indeed when patients with a solitary tumor less than 5 centimeters in size -many of whom had tumors of less than 3 centimeters in size - long term survival could be obtained. It had nothing to do with a tumor node or mets stage, but had to do more with small tumors without evidence of macrovascular invasion, and had a very nice four-year survival rate about 82 or 83%. Many of these patients, by the way, received preoperative chemo-embolization before they were transplanted, but you may remember in their paper that when they’d looked at those patients and compared those patients with and without chemo-embolization, there really wasn’t much difference. So they really couldn’t make a strong case for treating patients preoperatively with chemo-embolization.

These data are from the more recent Mayo data. Now after that drop back that I mentioned to you a moment ago, they became more selective and began to triple-image patients and do a better job of trying to identify those patients who truly had limited disease. The effort paid off showing that actually the disease-free survival exceeds actuarial survival here because of a couple of patients who died without recurrence and now show a pretty much straight line after the one-year point. And we found this data very encouraging. All of these patients were treated with a protocol, by the way, that included preoperative chemo-embolization. As I mentioned to you, we have a bias at Mayo that preoperative chemo-embolization, by reducing the amount of disease that may be transferable or left or spilled at the time of transplant, may be helpful. But we really can’t say that for sure at this point, even though these data are certainly very encouraging.
Liver Cancer

Liver Cancer

Hepatocellular carcinoma is one of the more common causes of cancer deaths worldwide. Not unexpectedly, the highest incidence of this disease is in hepatitis B endemic areas, although I think we all are expecting more of an impact from hepatitis C over the next few decades. As everyone knows, cirrhosis is a premalignant condition and as many patients in this country and around the world progress to cirrhosis it is somewhat unpredictable, I think, how much of a problem hepatocellular carcinoma is going to become, but I suspect it’s going to be more significant.
Cancer treatment
Surgical resection exists in those patients with well maintained liver function. Percutaneous ethanol injection, if you have a radiologist with a steady hand. Of course, orthotopical re-transplantation for a selected group of patients, chemo-embolization, transarterial chemo-embolization, or simply transarterial embolization without chemotherapy, and experimental medical therapy which is coming to the fore. And I’m not going to say much about this because currently there is little applicability with regard to these modalities. One reason why hepatocellular carcinoma, for example, may be somewhat resistant to treatment is because of the discovery of the multi-chemo resistant drug, or P-53 mutations, but all the patients with hepatoma don’t have P-53 mutations so simply inserting a wild-type P-53 is not necessarily going to help these patients. And then of course gene therapy. I think we are unfortunately away from routine applicability from any of these modalities.
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Liver transplantation for hepatoma initially gave poor results, unacceptable results, because these early studies basically included patients with advanced disease. I think that after this initial attempt, most people in the transplant community became disappointed and disillusioned about transplanting for this disease. However, after 1990 we began to understand that we simply had to be more selective in who was transplanted for hepatocellular carcinoma. Candidates are those people who have small tumors and of course poor liver function. In other words, people who would probably be headed for the transplant list even if they didn’t have a hepatoma. We are concerned about this issue of so-called field cancerization therapy, similar to scirrhous lung carcinoma, and that is; what happens if we actually perform a subsegmental or segmental resection for a patient who has hepatitis B, hepatitis C or hemochromatosis when we leave behind the fertile field that led to the development of that cancer, and it will likely lead to the development of another cancer? This issue of arising alpha-fetoprotein without detectable hepatocellular carcinoma tells us that this is a patient who should be moving toward a transplant program, likely. And finally, what is the role of preoperative chemo-embolization in these patients? I would submit to you that although we at Mayo are generally pro chemo-embolization, we have only preliminary data to suggest that it’s helpful.