Surviving Hepatits C-Related HCC and Cirrhosis

[eureka254]

At week 68 of treatment, we got the call that my husband's AFP had risen to 128:  the nurse was very concerned.  
Well, he had his CT-Scan Tuesday, and the doc says, at least for now,  he's in the clear :) ... no clearly defined liver tumor.   It was a tremendous relief, but the lead doc in the clinic came in and said that he was very concerned about future recurrence of hcc in my husband.  

The difficulty is that there are 'arterially enhancing lesions' that show 'mild interval change' -- stable for the most part, but a couple of them are showing larger measurements; however, the radiologist is attributing the differences to possible variations in 'timing and contrast.'  (Gee, they're done at the same place every 3 months, can't they be consistent?)  They might decide to draw AFP in the next month or two, but the doc wasn't too keen on doing any other tumor markers... an AASLD protocol kind of guy, I guess.

But, no bad news is good news, so all in all, it's still quite a miracle.  As of next week, my husband will be 3-years post-hepatectomy, 3-years cancer-free.  We asked the doc about any possible benefits for extending beyond 72 weeks, and again, an AASLD guideline answer:  no clear evidence as to any benefit extending beyond 72 weeks.  He did add, however, it was possible that extending might have benefits for my husband, but with no clear proof, he does not feel he could recommend it.  Bottom line, he left it up to my husband to decide, and stated that he would work with us whatever the decision.  (Well, that means it's research time for the next week and a half!  Btw, anyone with recent data related to tx-suppression of hcc, please share, I'd be most appreciative.)

The other remarkable thing is that in the last 3 years, despite not having a left lobe (they hoped it might regenerate some after surgery, but it did not), my husband's cirrhosis appears to remain stable:  no additional ascites, no organ enlargement (spleen, pancreas, etc.), no edema or other signs of decompensation.  It's hard to decide whether treatment played any role in keeping both decompensation and hcc at bay, so it makes us just a little nervous about stopping at the end of week 72... still on the fence (and running out of fence soon).

Just had to update anyone interested, release a little pressure, and thank you for reading/caring.

PS:
Part of me wanted to title this post "Interferon and Ribavirin Treatment after Anatomical Resection in a Cirrhotic Patient:  A Single Case Study" ;) -- but I decided the current title might be more help to anyone just diagnosed with any of the three (hcv, cirrhosis, or hcc) understand that NONE of those is a death sentence.  

[eureka254]

I've never heard of any indicated medical use or efficacy for IPT -- perhaps there's relevant statistics for other cancers, but I'm sure it would NOT be appropriate for hcc.  Since it's been well demonstrated that insulin administration can further exacerbate insulin-resistance in some people, I don't quite understand the rationale of insulin use in a population already at risk for IR.  In fact, considering the context of discussion (hcc suppression), insulin administration in the setting of hcc would NOT be a good fit for my husband at all:

From some recent clinical studies:
Liver International, Volume 30, Issue 3, 2010, Pages: 479–486, Takumi Kawaguchi, et al.
“Association of exogenous insulin or sulphonylurea treatment with an increased incidence of hepatoma in patients with hepatitis C virus infection."
Background: Diabetes mellitus is frequently seen in hepatitis C patients and is often treated with antidiabetic agents that increase serum insulin levels. Because insulin is a growth-promoting hormone, antidiabetic agents could pose a risk for hepatocellular carcinoma (HCC).
Aim: The aim of this study was to investigate an association between antidiabetic therapies and the incidence of HCC in hepatitis C patients with diabetes mellitus.
Methods: A nested case–control study was conducted. Participants were recruited from a cohort study, in which patients with hepatitis C were consecutively registered. Participants were assigned to an HCC group (n=138) or a non-HCC group (n=103). To identify independent factors, variables including use of antidiabetic agents were analysed by logistic regression analysis.
Results: Besides ageing, being male, cirrhosis and hypoalbuminaemia, use of exogenous insulin and a second-generation sulphonylurea were significant independent factors associated with an incidence of HCC [odds ratio (OR) 2.969, 95% confidence interval (CI) 1.293–6.819, P<0.0103 and OR 6.831, 95% CI 1.954–23.881, P<0.0026 respectively). In stratified analyses, the impact of these antidiabetic agents was more evident in patients who were non-cirrhotic than in those who were cirrhotic.
Conclusions: Exogenous insulin and a second-generation sulphonylurea were independent variables associated with an incidence of HCC in hepatitis C patients with diabetes mellitus. This association was evident in patients who were non-cirrhotic."

Of note, the authors write:
“Use of antidiabetic agents was a variable associated with a greater incidence of HCC in this study. Thus, we found a possible association between antidiabetic agents and the risk of HCC. Among antidiabetic agents, use of exogenous insulin and a second-generation sulphonylurea were significant variables associated with the incidence of HCC. Hyperinsulinaemia combined with insulin resistance is considered as a promoter for hepatocarcinogenesis and tumour growth (27, 28). Because exogenous insulin and a second-generation sulphonylurea increase circulating insulin levels, we hypothesize that the use of these antidiabetic agents accelerates the development of HCC in patients with HCV infection. “

In regards the second extrapolation, current research into cancer therapies related to virally-induced carcinoma as you mentioned are for the most part based on interrupting host-cell invasion and mutation; that would have little application in regards to hcv-hcc, since hcv is the only known RNA virus with an exclusively cytoplasmic life cycle, as opposed to encorporating host-DNA in its replication process.

[merryBe]

on the other hand, the mention of tumor targeting and chemo penetration brings up 2 newer developments....one is the use of insulin to soften up a tumor to accept more of the chemo drug....called IPT therapy, I wonder Willing what you think of this.
Insulin we know a key in opening the cell structure for nutrition, so it does make some sense, even though long term more insulin would lower interferon, I could see the use for specific tumor targets, coupled with INF supplementaion to compensate for the insulin load... it might be a good fit.
Certainly it would be a better fit for eureka's hubby whose lobe did not regenerate.
It might be worth a try before more resectioning is considered.

the other is extrapolation as employed by Inovio...whose new vaccine using this method eliminates 99% of the virus without toxic chemo.
Part of the key in cancer cells and viruses is penetration at the cellular level...the drugs capable of achieving greater penetration into our cells, and the virons themselves are the big pushes now.


care to comment on either of these methods?

[eureka254]

Appreciate your input.  For me it's personally compelling and scientifically fascinating stuff.  On one hand, I find it hard to ignore the data, but on the other, I also recognize that the low survival rates until recent years make for lack of any consistent long-term follow-up guidelines.  Up to this point, for the surviving hcc population, the small numbers have inclined towards heterogeneity in data, making most results speculative at best. (Treatment times in the hcc related studies varied from as little as 6 months to a median time of 55 months; doses varied, as did the type of IFN.)

Targeted genetic and molecular therapies have tremendous promise on so many fronts --  however, as it relates to hcv/hcc, it's definitely all new science and new medicine -- hopefully with a brighter future!  As I understand it, until recent years, study of both hcv and hcc was hampered by the lack of a stable cultured cell type fully permissive for HCV replication. Similarly, to date, only one cell type derived from human hepatoma has allowed for hcv replication, limiting investigative possibilities.  To further complicate issues, malignant transformation in hcc appears to have several possible pathways - both in the presence and absence of hcv replication.

The recent isolation of cultured cell lines has definitely prompted fervent research into the oncogenic potential of hcv viral proteins as well as viral activity.  It's good to know that other cancers are benefiting from molecular/gene therapies -- it hopefully means not too many years before it comes around for hcv-specific tumors.  (I'll have to keep an eye out for any promising literature on that.)  ~eureka

[willing]

thanks for posting. Though I'd read ifn was prescribed as a cancer med I had no idea the results in the case of hcc were so dramatic. Here's another recent meta-analysis reaching the same conclusion.

http://www.ncbi.nlm.nih.gov/pubmed/19672926

So it really is chemo after all.. It makes sense that the same cellular strategies used to shut down viral replication (eg stop translating) would inhibit out-of-control cellular proliferation. However the fact that ifn explicitly down-regulates oncogenes like c-myc  (which should have no role in enabling or eliminating viral intruders) indicates this is not coincidence but a distinct function.

This is all new to me, so I'm sorry but don't have any thoughts to contribute. However, I agree that it completely changes the rationale for continuing ifn and seems quite promising. An aspect that might be worth investigating is dosing - does one need to take as much of it as in its anti-viral role? Also, and there's a direct parallel with stat-c drugs here, helpful as ifn may be it's still heavy handed, non-specific intervention.

Some amazing results have been obtained recently by sequencing tumor cell lines and specifically targeting their idiosyncrasies . Here's a melanoma-related story:
http://www.nytimes.com/2010/02/23/health/research/23trial.html
I wonder if similar work has been done on hcc cells.

[merryBe]

aside from the iron and oxidative stress which I'm sure you are aware of, might I comment on the research Willing just brought to the table.

Obviously there is a reason that HCC has been on the rise besides HCV and HBV and it just now downed on me the obvious. Back in the dark ages, when I taught anatomy, it was well known even then as to what the role of the various macrophages and lymphocytes etc. were...the white blood cells and lymphatic system is the primary front line defense against aberrant and cancerous cellular growth.  And of course, as Willing just pointed out, Interferon interferes with HCC, because true to it's name, it is the component most known for fighting against these things. You may know interferon occurs naturally and after it's discovery in the blood it was then synthesized to be used, in the first few years as a first line chemotherapy for a variety of cancers.

that said, let's look at some other findings:

Like the fact that rats fed less calories live 1/3 longer lives than well fed rats.
Calorie restriction creates more health in several notable areas besides longevity, notably heart and cardiovascular health, endrocrine and pancreatic fucntion, and of course tumor suppression to name but a few.

Now lets add to that the recent studies showing that insulin cancels out interferon.

Add to that that we know that insulin production is directly tied to caloric intake....

And now, you have another
recipe for HCC prevention, namely calorie restriction.

I would encourage you and hubby to revisit CoWriter jounals about Insulin and IR.
Also:
As soon as you end treatment it would be very advantageous I would think to give consideration to these facts and this, my theory. Because as his interfeon levels go down after tx his ability to fend off aberrant cells could also decline, and the way to compensate for that would be to keep blood sugars lower and hence lower the amount of insulin constant in the blood stream. The level of natural interferon should thereby conversely go up in proportion to the decline of insulin levels.
The higher interferons levels will then help to prevent a reoccurance of the HCC.

A good book of how to eat well and not stave in the least and achieve this is by Dr. Barry Sear, it's called "he Zone".

This tactic, and the iron reduction should be a good start to keeping hubby HCC free after treatment. There is a plethora or iron reduction threads in here so I won't eleaborate this point.

Obviously additional fat intake also adds to oxidative stress, and so that also needs to be addressed. My method for this has been to add more omega fatty acids as these are known to reduce oxidative stress and also to help mitigate the oxidative load of other fats, such as saturated or animal source fats. Even if one is vegetarian the right components in the fatty acid chains have been shown to be beneficial so contrary to some old school thinking no fat is not the way to go. Fatty liver comes from too much of the wrong fats but not all fats are harmful, HDL fats are the GOOD GUYS and promote liver health.

I understand your wish to adhere to doctors orders, I did the same during tx...however some of the things I've learned or relearned since then have made me rethink some of their advice....for instance there are numerous compounds known to increase liver metabloism, decrease methylation, and collagen formation etc, which might have helped in both the treatment and aided n cellular penetration of the chemo into the liver cells as well...none of this is the focus of tradition western medicine....but of course, traditional medicine as a whole takes a dim view of things not requiring a prescription pad to dispense. Doesn't mean they are right always however, and it behoves the patients not to assume they always are, but to do our own research into the various claims and discover what nutritional changes or natural products might also aide us at the cellular level, IMHO..
best wishes to you both.

mb

[eureka254]

Glad for your interest!  Would be very curious to get some feedback on what you (and other readers) think of the relevant content in these articles.  I've got a few more recent ones in PDF format that aren't cutting and pasting well, but I'll try to get them posted when I find a way around that.

From:  Carcinogenesis, 2004, Vol 25 (3): 389-397.
“IFN-alpha prevents the growth of pre-neoplastic lesions and inhibits the development of hepatocellular carcinoma in the rat."  Nakaji, M., et. al.
Abstract: Interferon (IFN)-alpha treatment is a common therapy for chronic viral hepatitis and contributes to preventing hepatocarcinogenesis. However, it is not clear whether IFN-alpha directly inhibits the clonal expansion of pre-neoplastic hepatocytes. To clarify the mechanism by which IFN-alpha prevents hepatocarcinogenesis, we examined the effect of IFN-alpha in a chemically induced hepatocarcinogenesis model initiated by diethylnitrosamine (DEN) and promoted by 2-acetylaminofluorene (2-AAF) and partial hepatectomy, in which hepatocellular carcinoma (HCC) arises through pre-neoplastic foci without inflammation or fibrosis. The protocols of IFN-alpha administration were started simultaneously with chemical initiation and lasted for either 4 or 40 weeks. The pre-neoplastic foci and neoplastic HCC were evaluated at 4 or 40 weeks after chemical initiation, respectively. The effects of IFN-alpha were assessed by the expression of tumor-related genes and cell cycle-related genes in the pre-neoplastic foci, using immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). As a result of IFN-alpha treatment, the numbers and average volume of pre-neoplastic foci were reduced. The proliferating cell nuclear antigen index and the expression of G(1) cyclins were also reduced in the pre-neoplastic foci in the IFN-treated group.
The expression of p21, which is an inhibitor of cyclin-kinase complexes was higher in the foci of the IFN-treated group, while p53 expression was not altered in this group, compared with the control group. IFN-alpha also suppressed the tumor development at 40 weeks after initiation. And in the long-term IFN-alpha-treated group, both the tumor numbers and average tumor size were markedly more reduced than those in the short-term-treated group. Therefore, it was demonstrated that longer treatment with IFN-alpha was more effective, compared with shorter treatment. In conclusion, it was shown that IFN-alpha directly prevented and delayed hepatocarcinogenesis through the suppression of pre-neoplastic cell proliferation and that it may partially depend on p21 induction through a p53-independent pathway.  ISSN:  0143-3334.
Unfortunately couldn’t locate a free access link to the above article.

From:  The World Journal of Surgical Oncology, 2005, 3:27.
“Viral Hepatitis and Hepatocellular Carcinoma”
On page 10 it talks about “Anti-oncogenic effects of interferon-alpha”:
"HCC prevention by interferon-alfa might be the result of several direct or indirect mechanisms. Interferon has an antiproliferative and pro-apoptotic effect [174]. Interferon inhibits the expression of the c-myc oncogene and induces the expression of anti-proliferative factors and tumor suppressor genes [175-177]. In experimental animal models, the anti-neoplastic potential of interferon was demonstrated in already established tumors. In a transgenic mouse model it was demonstrated that early and prolonged administration of interferon diminished the severity of preneoplastic lesions and slowed down the development of HCC [178]. Interferon-alfa also could indirectly reduce the oncogenic risk by inhibition of synthesis of viral proteins which potentially dysregulate the cell cycle, and by enhancing the immune system eliminating not only infected hepatocytes but also initiated or fully malignant cells. Furthermore, interferon-alfa has an antifibrotic and anti-angiogenetic effect, which could also have an influence on tumor development [179].
Link to free-access full-article:
http://www.biomedcentral.com/content/pdf/1477-7819-3-27.pdf

From Oncology, 2008, Supplement, Vol 75, p30-41:
"Impact of Interferon Therapy after Curative Treatment of Hepatocellular Carcinoma."
"Primary and secondary prevention of hepatocellular carcinoma (HCC) which has become endemic worldwide in recent years are the most important issues in reducing mortality of HCC patients. Among several compounds previously reported for secondary prevention, treatment with interferon (IFN) is widely applied and shows encouraging results. To date, there have been 8 published randomized control trials (RCTs) and 6 published non-RCTs on IFN therapy after curative treatment of HCCs. Positive results were shown in 6 of 8 RCTs and in all of 6 non-RCT cohort studies regarding either recurrence rate or patient survival. The impact of IFN therapy after curative treatment of HCC can be summarized as follows: (1) HCC incidence of recurrence is reduced through viral clearance or long-term IFN treatment, even though HCV is not cleared. (2) Low-dose, long-term IFN (maintenance) therapy may suppress HCC recurrence through direct action of IFN on tumor cells. (3) Patient survival is improved through  growth inhibition of recurrent tumors, as well as preservation of liver function. (4) According to the above 3 points, there is more chance to receive curative treatment in the IFN than the non-IFN group. (5) Pegylated IFN (PEG-IFN) may be more beneficial than non-PEG-IFN products since IFN concentration is maintained in the body at a high level, which is favorable for its action as a direct anticancer agent. (6) It may be concluded that IFN treatment after curative treatment of HCC is beneficial at least in HCV-related HCC, since it lowers recurrence and improves survival. Copyright (c) 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]r curative treatment of HCC can be summarized as follows: (1) HCC incidence of recurrence is reduced through viral clearance or long-term IFN treatment, even though HCV is not cleared. (2) Low-dose, long-term IFN (maintenance) therapy may suppress HCC recurrence through direct action of IFN on tumor cells."
Free access to full article:
http://content.ebscohost.com/pdf9/pdf/2008/NK2/02Nov08/35755741.pdf?T=P&P=AN&K=35755741&EbscoContent=dGJyMNHr7ESep7I4y9fwOLCmr0ieprFSr6u4Sq%2BWxWXS&ContentCustomer=dGJyMPGrr06yqLFRuePfgeyx%2BEu3q64A&D=aph

Just a few items that gave me cause for pause about my husband stopping IFN completely.  Any thoughts?