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419309 tn?1326503291

Surviving Hepatits C-Related HCC and Cirrhosis

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.  
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Avatar universal
I can see where open-ended continuation of the fun and games would be a challenge. Given that the goal at this point is cell-death of any possible malignant cells rather than anti-viral, one approach might be a 3 month break, check on SVR and then return to the grind. Also, though the Japanese trial seemed essentially identical to SOC dosing,  the studies above make a case for mono-rbv or its use in conjunction with other agents (MPA) - which might make for a more bearable regimen. I much admire the attitude you're both bringing to this fight. In case I ever grow up ( looking less and less likely) it will  be a model to remember.

(BTW that Hepatology monotherapy cite was a poster presentation (1214) from the '03 AASLD. Not likely there's any text to find; but it might be worth writing the authors
(Manuela Neuman, University of Toronto, Toronto, ON, Canada; Cyril Bonaventure, Marianne Maynard-Muet, Christian Trepo, INSERM 271 & Service d’Hepatologie, Lyon, France)


Thanks for clarifying the annual risk numbers; grim as they are, I think they're one of the more compelling arguments I've seen for treating sooner rather than later "Among patients without cirrhosis, the annual risk increases as the stage of fibrosis increases (F0 or F1 [none or minimal portal fibrosis] = 0; F2 [periportal fibrosis] = 1.5%; F3 [bridging fibrosis] = 5.1%) (15)"
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419309 tn?1326503291
Of note, I did not address the possible benefits of riba with my husband’s doctor (due to what I felt was a lack of significant citations), but he did call last week to say that he felt the evidence did point to INF having beneficial impact in the case of hcc, though such benefit would be impossible to quantify.  He stated he would not have hesitated to advise continuing if it were not for my husband’s significant side effects, and expressed concern about my husband’s ‘suffering’ through treatment (last week hgb was 9.8 even with procrit 2x/week, and platelets were 38).  It looks like it’s going to boil down to how my husband feels on any given Friday night… so much for scientific method…

My point in addressing GD’s numbers was to stress that the statement “…the HCV rate… 25% to 50% of us reading this..” appeared to reference the newly diagnosed (all hcv-ers), not just cirrhotics.  Assuming 1000 new hcv diagnoses, with a 10-20% rate of cirrhosis in 20 years, I was emphasizing low risk annually for the general hcv population to develop hcc.  Statistically speaking, presuming a 5-10% rate of cirrhosis at 10 years, risk factor would be:
1/20(10-yr rate of cirrhosis) x 5/100(rate of hcc) = 1/400 annual risk for hcc in the general hcv population

No misunderstanding, actually -- my concern was language, not statistics:  if GF had said “25% to 50% of us CIRRHOTICS reading this…” that would have been a fairly accurate assessment, as you pointed out.  Presuming again a population of 1000 hcv’s, in 10 years we’d have ~25 cases of hcc out of 50 cases of cirrhotics, and indeed at 20 years it’d be ~50 cases of hcc out of 100 cirrhotics (perhaps with attrition of numbers due to esld impact.)
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Avatar universal
so humble old ribavirin is actually a regulator of cellular guanine concentration, and the GTP/GTP depletion triggers cell-death pathways; who knew the stuff had so much pull! (Some) of the anti-viral pathways of ifn are fairly well worked out, but this rbv effect looks like fairly new work. On a practical level, it's certainly good motivation to keep up that maintenance dosing, if that's the chosen path.

BTW, I didn't understand your comment to GD about the cumulative cirrhosis-hcc stats. Assuming we have 100 cirrhotics at an annual reunion, and a 3% incidence of hcc, the total  number of cases over 10 years seems to be (with  minor rounding error)
0 100 0
1 97 3
2 94 5
3 91 8
4 88 11
5 85 14
6 83 16
7 80 19
8 78 21
9 76 23
10 73 26
so by the 10th year a quarter have reached an hcc, as GD noted. The 3% annual risk seems in line with current estimates, eg
http://www.ncbi.nlm.nih.gov/pubmed/18628926
For a 5% annual risk factor, 20 years out I get 64% with hcc. Am I  misunderstanding the annual risk calculation or is it time to be here now?
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419309 tn?1326503291
HectorSF:
The "What have I got to lose?" philosophy can get some return! :)  Thanks.

willing:
Admittedly, I was excited to receive the response though a little surprised by the details.  I, too, was expecting a long-term maintenance approach, but it appears to be SOC as it relates to hcc and not much more. Of note, when my husband first approached treatment, he was told hcc recurrence would preclude him from inf/riba, so perhaps this protocol is to address the safety of continued inf/riba during active hcc...

As I'm sure you know, the mechanism by which Interferon works (or doesn't work) is not well-understood, and what I find is with ribavirin, it is even less so. There are at least a couple dozen good pieces of literature on INF-induced cell mechanisms, but precious little on riba, less than a handfull:

"Ribavirin Acts via Multiple Pathways in Inhibition of Leukemic Cell Proliferation"
Citation: ANTICANCER RESEARCH 29 (6): 1971-1980 JUN 2009
"Abstract: The aim of this study was to elucidate the anticancer activity of Ribavirin, an antiviral drug and a known inhibitor of inositide-5'-monophosphate dehydrogenase. Materials and Methods: Using human cancer cell lines, the potential of the drug to inhibit growth and induce the apoptotic and differentiation pathways was investigated by cytological methods. The effect exerted upon gene expression was studied in K562 cells by Q-PCR. Results: Treatment with Ribavirin resulted in a significant growth inhibition (IC50=15 mu M) via activating apoptosis and the differentiation pathway in K562 cells. It also modulated the expression of about 60 out of 85 genes having roles in cell proliferation, purine biosynthesis, translation initiation, oncogenic signaling and cell survival (p<0.05). Conclusion: Ribavirin is a potent anticancer agent, being a strong inducer of apoptosis and a moderate inducer of differentiation in K562 cells. These effects are mediated through the modulation of key molecular and metabolic pathways."

"Molecular targets of guanine nucleotides in differentiation, proliferation and apoptosis"
Author: Yalowitz, JA
Citation: ANTICANCER RESEARCH 20 (4): 2329-2338 JUL-AUG 2000
"Abstract: Guanine nucleotides are important substrates for macromolecular synthesis, cell signaling, and integration of metabolic status and have an evolutionarily conserved role in differentiation, proliferation, and apoptosis. Bacteria, yeast, and mammalian cells are all dependent on an adequate supply of guanylates to maintain proliferation. Depletion of intracellular guanylates, especially by inhibition of de novo synthesis via the IMP dehydrogenase pathway, is a potent signal for inhibition of proliferation as well as apoptosis. Growth inhibition by depletion of GTP is a conserved pathway from humans to Bacillus. IMPDH expression is downregulated by the p53 tumor suppressor gene. Many inhibitors of IMP dehydrogenase are used as clinical agents. These agents are antivirals (ribavirin), antitumor (tiazofurin [TR], selenazofurin [SR], and benzamide riboside [BR]), and immunosuppressants (mycophenolic acid [MPA]). The biochemical actions of IMP dehydrogenase inhibitors are well known, but correlation with in vivo activities is difficult because the extent of erogenous contributions to the nucleotide metabolic pathways is not fully known. IMPDH inhibitors are biochemically convenient in inhibiting parallel pathways, since excess reactants IMP and 5'-phospho-ribose-1'-pyrophosphate (PRPP) inhibit guanine salvage synthesis. IMPDH activity is a progression-linked key enzyme in tumorigenesis. The antitumor potential of IMPDH inhibitors is therefore particularly high."

"An atypical necrotic signal induced by immunosuppressive and anti-viral agents"
Author: Chaigne-Delalande, B
Citation: AUTOPHAGY 5 (3): 425-427 APR 1 2009
"Abstract: We recently demonstrated that the anti-viral agent ribavirin and the immunosuppressor mycophenolic acid (MPA) are both potent inducers of a necrotic signal. These two chemicals deplete the intracellular pool of guanosine triphosphate through the inhibition of inosine monophosphate dehydrogenase (IMPDH) activity. The cellular stress resulting from the GTP/GDP depletion leads to the activation of the small GTPase Cdc42 and the remodeling of actin, which are crucial events in the transmission of the MPA-mediated necrotic signal. Nevertheless, we observe for each tested cell (leukemic T and B-cell lines, activated PBLs) that a minor part of the cell population is killed through a caspase-dependent apoptotic signal. Blockade of the caspase activity eliminates the apoptotic cells, which are replaced by cells exhibiting autophagic features. In light of our findings, we assume that the newly characterized atypical cell death induced by MPA may account for the decreased risk of cancer occurrence observed in transplant recipients treated with mycophenolate mofetil (MMF) versus a non-MMF regimen."

The one article most that caught my eye most but I've been unable to dig up yet is:
"Ribavirin monotherapy promotes signaling for apoptosis enhancing caspase activity in patients with chronic hepatitis C." Author: Neuman, M
HEPATOLOGY 38 (4): 1214 Suppl. 1 OCT 2003
If I find it and it turns up anything of interest, I'll post back in.

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Avatar universal
congratulations ! now we'll have to petition MH to get you one of those nifty caduceus icons...

the protocol is quite different from what I would have expected. Instead of low dose, maintenance mode ifn only, it looks like full-bore(if you can tolerate it), for a limited time, and with rbv thrown in. The rbv in particular, is surprising. Have you seen any indications that rbv's immuno-modulating function would bear on inducing hcc apoptosis?
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446474 tn?1446347682
"Dear Dr. Eureka" - nice work!!!  ;-)
Being pro-active can really payoff. The worst that can happen is we are ignored or told no. There are people out there who are willing to share and help, if we just take the risk and asked for help.

Your persistence is inspiring.

Best-

HectorSF
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419309 tn?1326503291
I was pleasantly surprised when I received a response from the investigator today, and thought you might be interested to see his response:

"Dear Dr. *Eureka*" (the incorrect assumption there made me chuckle a bit)
"Thank you very much for your e-mail on March 19. I can explain our treatment
protocol briefly;
The patients with curative surgical resection or curative RFA treatment for
primary HCC are enrolled to our protocol. Combination therapy with
peg-interferon (IFN)-alfa-2b (1.5 ug/kg) and ribavirin (600-1000mg) was
given to the cases with haemoglobin level higher than 12 g.dL, a platelet
count higher than 100000/ul, and a neutrophil count higher than 1500/uL. If
the patient show haemoglobin level higher than 10 g.dL, a platelet count
higher than 80000/ul, and a neutrophil count higher than 750/uL, he(she)
will be treated with peg-IFN (1.0 ug/kg) and ribavirin (400-600mg). The
remaining case (for example, haemoglobin level is 9.0 g/dL) might be treated
with peg-IFN (0.5 ug/kg) and ribavirin (200mg). The treatment is continued
48-72 weeks.
I hope this information may help your understanding of our clinical study."

Indeed, as you predicted, the dosing/frequency information was shared readily, and again, I can't thank you enough for the link (even if I was slow to infer the obvious :D).  ~eureka
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Avatar universal
good move! sorry, I should have added to the post that the relevance is not participation in the trial but contacting them, particularly re dosing/frequency. I can't imaging they wouldn't make the protocol available, it's usually posted with the trial description. Size of the trail is no doubt quite small, so I'd expect they would also be interested in following up with you.
Helpful - 0
419309 tn?1326503291
willing:
At first I dismissed the trial for obvious geographical reasons, but it stuck in my mind and made me decide to take a rather forward step (see below).

HectorSF:
The Ishikawa notes further motivated me to press further, to do a little bit more investigating, and to dig a little deeper.

The result is the following email I composed and actually sent out tonight:

"TO: Chief Investigator
RE: Clinical Trial #NCT00375661
Title:  Low-Dose Peg-Interferon Plus Ribavirin (IFN/RBV) for Prevention of Hepatocellular Carcinoma (HCC) Recurrence in Patients Who Had Surgery to Remove Primary HCC

Dear Doctor Marusawa:

This letter is written to express my very personal interest in the details of your current Phase IV clinical trial referenced above.  I have been reading data presented by Kudo [1,2], Kurokawa [3], and Ishikawa [4] and would very much like to learn more about your research protocol.  To my knowledge you are the only medical center currently enrolling patients for this trial, and I hope you might provide me with additional specifics beyond what is noted at the website www.clinicaltrials.gov.

If the actual protocol is not available for sharing, I would still be most interested in the informed patient consent and/or the proposal submitted to obtain protocol approval. If none of the items mentioned are available for public view, any details you might provide in regards to the management guidelines for the non-control group would be very much appreciated.

I am most eager to see the results of those in your Interferon maintenance group. I look forward to your response and would be most grateful for any information.  Thank you for your time and consideration.

Yours truly,
"eureka254" (real name, of course)
(Title, Company, Address)
USA
Tel: XXX-XXX-XXXX
Fax: XXX-XXX-XXXX

References
1 Kudo M, Sakaguchi Y, Chung H, et al:  Long-Term Interferon Maintenance Therapy Improves Survival in Patients with HCV-Related Hepatocellular Carcinoma after Curative Radiofrequency ablation. Oncology 2007;72(suppl 1):132-138.
2 Kudo, M.  Impact of Interferon Therapy after Curative Treatment of Hepatocellular Carcinoma. Oncology 2008;75(suppl 1):30-41.
3 Kurokawa M, Hiramatsu N, Oze T, et al:  Effect of Interferon alpha-2b plus ribavirin therapy on incidence of hepatocellular carcinoma in patients with chronic hepatitis. Hepatology Research 2009;39:432-438.
4 Ishikawa T:  Secondary prevention of recurrence by interferon therapy after ablation therapy for hepatocellular carcinoma in chronic hepatitis c patietns.  World J Gastroenterol 2008;14(40):6140-6144."

Thanks to you guys for planting the seed and giving me the impetus to step outside my usual comfort level in hopes of finding some answers.  It'll be interesting to see if I get any response... I'll keep you posted.
~eureka
Helpful - 0
446474 tn?1446347682
Here is excerpts from a pdf with info related to HCC and Interferon from Japan (related to Willing's info) that may be helpful. It appears that Japan is doing some work in this area and future studies are to be conducted with both Interferon AND ribavirin to see if the combination helps to prevent recurrence of HCC.

The World Journal of Gastroenterology
Received March 31, 2008; Revised May 13, 2008; Accepted May 20, 2008.
"Secondary prevention of recurrence by interferon therapy after ablation therapy for hepatocellular carcinoma in chronic hepatitis C patients"
http://www.wjgnet.com/1007-9327/14/6140.pdf

Toru Ishikawa, Department of Gastroenterology and Hepatology, Saiseikai Niigata Second Hospital, Niigata 950-1104, Japan

PRIMARY PREVENTION OF
HCV-RELATED CHRONIC HEPATITIS
BY IFN THERAPY
Many studies have documented that IFN significantly suppresses the onset of HCC from chronic hepatitis and liver cirrhosis. Studies have found that IFN therapy for
HCV infection is useful in suppressing carcinogenesis and improving liver function[13,14] and that IFN therapy eliminates HCV RNA and clearly suppresses the onset of HCC in patients with normalized transaminase levels[15]. Additionally, even if a complete response is not achieved, IFN therapy suppresses HCC when compared
to untreated cases[16]. Furthermore, even in the presence of advanced
chronic hepatitis, cirrhosis improves in about half of patients with a sustained response to IFN therapy[17], and IFN therapy lowers transaminase, maintains platelet
counts, and reduces carcinogenesis[13]. This suggests that IFN suppresses persistent hepatitis in liver cirrhosis and carcinogenesis. Regarding the onset of HCC, it is not clear if it is important to maintain low transaminase
levels or suppress liver fibrosis, but it is highly likely that blocking fibrosis is important in suppressing carcinogenesis. Therefore, IFN therapy appears to
prevent liver fibrosis in liver cirrhosis. Ever since the national health insurance system
beg an covering IFN therapy in 1992, antiviral therapy for hepatitis C has steadily advanced and at present, therapy combining PEG-IFN and ribavirin is
considered the most potent. The combination therapy was markedly effective in about 90% of patients with genotype-2 HCV when administered for 24 wk[18], and
it was markedly effective in about 50% of patients with intractable hepatitis (genotype-1 HCV or high viral load) when administered for 48 wk[19]. In Japan, PEG-IFN and ribavirin combination therapy has improved the
therapeutic results for intractable chronic hepatitis C.

IFN THERAPY AS SECONDARY PREVENTION FOR RECURRENT HCC
IFN therapy has been performed to prevent recurrent HCC (Table 3). One study retrospectively investigated recurrence after curative resection of HCV HCC, and
found that alanine aminotransferase levels remained high[20]. In other words, hepatocyte necrosis and inflammation appear to be closely involved with
recurrence. If IFN is successful in lowering HCV to an undetectable level, necrotic inflammation is naturally improved. At the same time, carcinogenesis is believed
to be suppressed even in biochemical responders.Ikeda et al[21] have investigated the suppression of recurrent HCC by IFN-β following surgical resectionor PEIT for HCC in patients with HCV cirrhosis. They have reported that intermittent IFN-β administration following surgical resection or PEIT for HCV HCC
suppresses recurrence.

Kubo et al[22] have conducted a randomized controlled trial of postoperative IFN therapy in patients with HCV HCC and have reported that the rate of recurrence is
significantly lower for patients with IFN therapy.Suou et al[23] administered 6 MU of IFN-α for 24 wk and reported that the 3-year survival rate for patients without IFN-α was 18% and that of patients with IFN-α was 63%. Additionally, Shiratori et al[24] have reported that while IFN therapy does not markedly lower the rate of recurrence the first time, it significantly lowers the rate for the second and third times. Hence,
IFN may initially act on tumors to suppress intrahepatic micrometastases following therapy for HCC, and then it may act on the virus to suppress recurrence 3-5 years
later. Furthermore, it is reported to the contrary that although the cumulative recurrence rate in the IFN group was found to be lower than in the control group during
the first 3 years after commencement of IFN administration,the recurrence rate in the IFN group increased with the lapse of time over 3 years. However, longterm,
low-dose, intermittent IFN therapy successfully delayed clinical recurrence of HCC after radical RFA therapy[25]. In these studies, IFN therapy consisted of
non-PEG-IFN monotherapy and the rate of sustained viral response was low, at 13%-33%. Therefore, if PEGIFN and ribavirin combination therapy further improves
antiviral effects[26], then recurrence may be suppressed even more. However, many patients with HCV HCC are elderly or have cirrhosis, and the dose and duration of
PEG-IFN and ribavirin combination therapy have not been established in these patients. Further investigations are warranted.
IFN therapy following therapy for HCC is safe in selected patients. However, IFN therapy for the prevention of recurrent HCC is different from that for the treatment
of primary HCC. Because prevention involves not only inflammation, fibrosis, and HCV, but also HCC related factors, further investigations, including randomized
controlled trials, are needed. Furthermore, antiviral therapy itself may improve liver reserve and expand the therapeutic options at the time of recurrence, thus improving
the prognosis of HCC, and this issue also needs to be addressed by further studies including randomized controlled trials.

....CONCLUSION
Secondary prevention of HCC is an important clinical issue because the recurrence rates of HCC are extremely high even after effective local treatment with hepatic resection or percutaneous ablation. This involves multicentric carcinogenesis in which new lesions are formed as a result of underlying hepatitis. Therefore, IFN therapy following the treatment for HCC is safe in selected patients and IFN therapy is an effective secondary prevention. In the future, PEG-IFN and ribavirin combination therapy may prove to be effective in preventing recurrence, and further investigations involving more cases are needed.

Cheers!

HectorSF
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Avatar universal
eureka254:  you've probably already seen this, but just in case
http://clinicaltrials.gov/ct2/show/NCT00375661
is a clinical trial  out of Kyoto looking at maintenance ifn in hcc. I think there's a lot of work with hcc in Japan/China because of the higher rates. Also,  a recent  possible counter-indication
http://www.ncbi.nlm.nih.gov/pubmed/20213095


MB : I keep meaning to read more about the whole HCVmetabolic syndrome connection, but haven't yet. Thanks for the references.  
Though an inverse link between high-BMI/high-HOMA and SVR seems strong, the HCVIR association seems less clear. What's causing what?

Here's a recent analysis of Halt-C data documenting a drop in HOMA among those in whom ifn triggered VL reduction - ie eliminating HCV reduced IR.

http://www.ncbi.nlm.nih.gov/pubmed/20156586
see also
http://www.medscape.com/viewarticle/578611_4
Helpful - 0
476246 tn?1418870914
I am not knowledgeable of all these things....

Just wanted to send you a lot of love and good vibes. You guys are fighting a tough battle and my heart goes out to you.
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419309 tn?1326503291
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.
Helpful - 0
233616 tn?1312787196
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?
Helpful - 0
419309 tn?1326503291
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
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Avatar universal
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.
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233616 tn?1312787196
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
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419309 tn?1326503291
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?
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Avatar universal
yes - please post what you found - had no idea ifn was effective as an anti-hcc agent. I'd guess ignorance rather than lack of interest  applies, at least in my case.
Be well.
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419309 tn?1326503291
willing:
Thanks for your response... means a lot coming from you.  Some nice slide presentations there... appreciate the link!  The question of extending in our minds is less related to SVR success rates and more related to the suppessive possibilities of IFN on hcc.  There appears to be some kind of link between the cytokine receptors in hepatocytes and their activity during immune response that prevents over-expression of mutation genes, which is common in the development of hcc. I don't presume many people to have much interest in hcc necessarily, but if you'd like me to post what I've found recently, let me know I'd be more than happy to do so.

Trish:
Thanks for making me smile.  It's good to know there are people out there that appreciate our special brand of oddity ;).
The true fear in our minds is that even reaching SVR doesn't clear him from hcc recurrence -- it definitely improves his odds, but he'll still not be clear of the cloud of hcc by a long shot.  The difficulty in sorting out all the halt-c and ideal trials is the short follow up period we're in -- we don't have the advantage of long perspective as yet.  Most of the data relates to non/null responders, but there's still some discussion about the SVR population (which I hope my husband is!), and why it isn't completely 100% successful in preventing decompensation in some cases and what role maintenance therapy might play in closing that gap.  Finding myself continuing to dig into the 'annals of hcv' ... ;).

Fondest and best regards to you both.  ~eureka
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Avatar universal
"Definitely a good way to combat anxiety: with positive thinking.  It’s reassuring to know that my husband and I may not be as odd as we thought we were.  :: ) Thanks. "

Eureka, I think you and your husband are every bit as odd as you think you are and I say that with a great deal of affection, admiration and respect.  I always marvel that the two of you have found each other.

I'm sure you've seen this article with all the research you do.  I'm including it anyway.  To be taken in context, of course.  I'm no expert, it's simply an article I came across and thought it might add and hopefully not detract.

http://www.natap.org/2009/HIV/062109_01.htm

"The Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) study is a prospective, randomized, investigator-initiated study to determine whether maintenance therapy with low-dose pegylated interferon alpha in patients with chronic hepatitis C who had failed to clear virus following a standard course of treatment would slow the progression of disease.1 Progression of disease was determined on biopsy and by the development of the end-stage complications of progressive hepatitis C, namely development of hepatocellular carcinoma (HCC), liver failure, and the need for liver transplant. Previous reports from the HALT-C study have indicated that this treatment regimen did not halt progression of liver disease.1 In a report in this issue of Gastroenterology, Lok et al2 provide evidence that the incidence of hepatocellular carcinoma is also not different in those who were on maintenance therapy versus untreated controls. These results are in contradistinction to an earlier report on 2-year maintenance therapy in nonresponders.3 However, the sample size in this study was small and may have led to type 1 error.3"

Sometimes I wonder if getting off treatment is similar to starting treatment.  I remember just before I started treatment, I felt as if I was about to step into an elevator, the doors would close behind me and I would not be able to get off once I got on and it was going to be a very long ride. Perhaps getting OFF treatment is like that for some people who have so much more at stake than I did when treatment stopped.  You can only hedge your bets so much.  At some point, you have to step OUT of the elevator and get back into the stream of things again.  At some point, you WILL have to cut the treatment tie and ride the wave.  I have no idea when that is for you and your husband.  I just wish you great wisdom in figuring that out .. and then serenity as you proceed with your choice.  I'm really believing and hoping for that big SVR "Huzzah!!!" to come along for both of you afterward.

Fond regards,

Trish
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419309 tn?1326503291
tashka:  
I did work up the nerve to ask the doc about more serum screening, AFP L3 and DCP – both of which are readily available at the lab my husband goes to – but the lead doc didn’t hesitate to point out that he doesn’t see value in either because the results would have no “clinical application,” and he’s absolutely right.  He’s a real by-the-book guy.

Willy50:
Interesting consideration… half dose.  Hmmm…
I guess if there were an FDA-approval of PIs slotted for this fall he’d feel better about stopping at 72 weeks, but all views seem to point to viral activity as a main contributor in hcc.  I guess in essence treatment is a (very itchy and irritating) ‘Linus” blanket, as a good friend once said.  Being that my husband has surpassed both his ‘expected recurrence time’ and ‘expected length of survival’, it begs the question of treatment’s contribution to the mix.  His history of hcc and the existence of lesions currently below hcc guidelines make us anxious about giving up any room for viral activity.  We’d be forever second-guessing if we stopped and things took a turn for the worse.  

copyman & tashka:
No question that MRIs would be better than the repeated CT Scans, but my husband does not have the option to do MRIs, having retained schrapnel pieces from injuries during combat in Vietnam (back then, the military just ‘patched them up’ and sent them back into the field). He was actually thinking about going to 6-month intervals in between, but doc and nurse said not advised because of existing lesions and continual climb in AFP.  A 6-month interval could conceivably allow a tumor to develop enough to place him out of transplant eligibility, hence the close surveillance.

HectorSF:
Great seeing you back here – hope you’re doing ok and glad you’re still holding your own.  It’s definitely been a lot of anxious watching the last few years but considering all, we’re glad for every small reprieve.  Because ultrasound would not be able to distinguish the characteristics of ‘tumor’ from lesion, docs don’t consider it useful in my husband’s case.  It’s a bottom-line numbers waiting and numbers game:  the chances of getting cancer from CT-Scan are considerably lower than the 80% risk of recurrence within 3 years the docs expected.

merryBe:
We’re actually sucking it up and pretty happy with the news, considering everying; it could have been much worse.  Hubby’s doc doesn’t like the idea of adding too much to the mix during treatment (even had to twist his arm for Alinia), but I have to respect that the guy is head of two viral treatment clinics for good reason.

portann:
Really nice of you to check in and thanks for the kind words.

nygirl7:
Made me chuckle to think that biochemically my husband and your mom have something in common – appreciate your friendship and encouragement – you’re proof that New Yorkers are all heart. :)

justme53:
See, it ISN”T just you! : )  You nailed it... and neither my husband nor I relish the idea of walking the current highwire without a safety net : |

RCM829:
Definitely a good way to combat anxiety: with positive thinking.  It’s reassuring to know that my husband and I may not be as odd as we thought we were.  :: ) Thanks.
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Avatar universal
you two are an inspiring and remarkable pair! All the best.

There's a couple of good HCC presentations, one by Hashem El-Serag another by Masao Omata as part of the HCV DART 09 talks:
http://ihlpress.com/gaj_hepdart2009.html

regarding maintenance, I seem to recall there was some question about the (negative) results of halt-c/copilot. See for example

"Thus, long-term maintenance therapy may be beneficial in confirmed nonresponders with portal hypertension."
from
"Management of Chronic HCV : Maintenance Therapy for Nonresponders and Relapsers"
http://www.medscape.com/viewarticle/713174_7

It's easy to understand not wanting to risk that HUGE 72 week investment at this point. However, close monitoring of the HCC seems the more important issue. If relapse happens, its impact on  cirrhosis progression will likely be slow and the options for another attack with stronger meds are promising.
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Avatar universal
I can certainly relate with what justme53 just said...my 72 weeks is coming to an end in July and I feel a tremendous sense of anxiety about that. Yes, I will feel better but...
As long as I'm treating - and undetectable -  I somehow feel  as though I'm winning this. I think the best way of looking at all this is - and here I go again - that this will be a cureable disease one day soon, and we will all be rid of it.
Until then, keep up exactly what you are doing.
And yes, we are interested and care about you both and appreciate the updates
Big smile to you!.  
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