Aa
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.
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.
I am so happy to hear this good news! I think, periodic retesting of AFP would be a good idea. Did the doctor test AFP L3? It is pretty specific.
Good luck with treatment.
Good luck with treatment.
I wonder, since his tumor marker is climbing and you appear to want to prolong TX, whether you might ask about "suppressive therapy"?
This is one area in which you may have a little wriggle room. The idea would be that he might taper to something like half dose and maintain the status that he has achieved, if only for a little longer. That might get him closer to the approval dates of either of the PI's which may become available in the next year.
The very good news is that in general, if one is able to respond to TX one should also be an even better responder with the addition of a PI. We don't yet know when they will be approved but if one could s-t-r-e-t-c-h his therapy out one could get closer to the approval date.
Understand, I'm not recommending this, but it may be an option to discuss with the doctor.
best,
Willy
This is one area in which you may have a little wriggle room. The idea would be that he might taper to something like half dose and maintain the status that he has achieved, if only for a little longer. That might get him closer to the approval dates of either of the PI's which may become available in the next year.
The very good news is that in general, if one is able to respond to TX one should also be an even better responder with the addition of a PI. We don't yet know when they will be approved but if one could s-t-r-e-t-c-h his therapy out one could get closer to the approval date.
Understand, I'm not recommending this, but it may be an option to discuss with the doctor.
best,
Willy
great news! sorry i can't help much with extending TX but I don't think there is much data out there on this.
personally i would be concerned with getting CT's every three months. i have read where having these can give you cancer.
Perhaps doing an MRI every other time would be better.
Best of luck
personally i would be concerned with getting CT's every three months. i have read where having these can give you cancer.
Perhaps doing an MRI every other time would be better.
Best of luck
Yes, I agree with copyman, CTs every 3 months is way too much. It is a huge dose of radiation. Because your husband already had cancer, such radiation exposure can cause its progression. Radiation is a very well known cancerogen.
MRI would be better, because it doesn't involve radiation at all. It costs more than CT, so often insurance doesn't want to pay for it. But if your husband needs such frequent monitoring, your doctor can justify MRI to insurance company.
MRI would be better, because it doesn't involve radiation at all. It costs more than CT, so often insurance doesn't want to pay for it. But if your husband needs such frequent monitoring, your doctor can justify MRI to insurance company.
Glad your husband is clear of HCC and it sounds like his cirrhosis is under control. It is always better to check, just in case. Even though I know it is worrisome. It is always better to catch anything going wrong every as there are more options at that point.
I believe the standard imaging protocol now is to switch between a sonogram and CT every 6 months. At the same time get a liver panel to see if anything has changed significantly since the last blood test, That is what I have been doing for a couple of years since learning I am stage 4.
As far as AFP...it is not an accurate marker for HCC. My AFP is always over 100 and varies each time I am tested. I have heard that if it progressively rises or goes above 400-500 this would probably indicate the presence of HCC even if it couldn't be seen using imaging.
"With regard to hepatocellular carcinoma, AFP cannot be considered to be specifically diagnostic of HCC, as levels of AFP may be elevated in serum from patients with chronic liver disease; for example, research has indicated that AFP is not useful for screening in patients suffering from cirrhosis or Hepatitis C and therefore elevated AFP in these patients may not be indicative, or be only suggestive, of HCC".
Best-
HectorSF
I believe the standard imaging protocol now is to switch between a sonogram and CT every 6 months. At the same time get a liver panel to see if anything has changed significantly since the last blood test, That is what I have been doing for a couple of years since learning I am stage 4.
As far as AFP...it is not an accurate marker for HCC. My AFP is always over 100 and varies each time I am tested. I have heard that if it progressively rises or goes above 400-500 this would probably indicate the presence of HCC even if it couldn't be seen using imaging.
"With regard to hepatocellular carcinoma, AFP cannot be considered to be specifically diagnostic of HCC, as levels of AFP may be elevated in serum from patients with chronic liver disease; for example, research has indicated that AFP is not useful for screening in patients suffering from cirrhosis or Hepatitis C and therefore elevated AFP in these patients may not be indicative, or be only suggestive, of HCC".
Best-
HectorSF
Gee, we go through so much with this chemo...it just suc.ks when insult is added to injury. So sorry to hear this news for you two.....
I'd strongly suggest he stick with MRI's as CT's x ray hundreds of times and are very damaging. Not only my doctor, but another doc/radiologist I know who has this both concur here.
Beyond that, no saturated fats, or hydrogenated, and low iron diet with regular iron panels and supplements to block iron absorption, those are the main preventatives. If you can get him to give up nitrates that helps too (cured meats), and cigs of course. Lots of things go into why cancer markers go up but they can come back down as well. I used CoQ10 for mitochondrial repair, branched chained amino acids also have shown repairative benefits.
Hi Eureka,
Thanks for sharing all this.
I'm no use when it comes to the complex situation you're in but I so admire you for the amazing woman you are and how the two of you are in this together.
Best to you both,
xoxo
Susan
Thanks for sharing all this.
I'm no use when it comes to the complex situation you're in but I so admire you for the amazing woman you are and how the two of you are in this together.
Best to you both,
xoxo
Susan
My mother has had for 20 years extremely high AFP numbers. No HCC, tumors, growths, nothing they could find. Then one day it just leveled out. Strangely odd.
I'm so glad for your good news Eureka. I don't know if there is any data out there for extending past 72 or if it even correlates to someone who had HCC not just HCV. I do think perhaps tapering to a maintenance dose to keep things in check while waiting for the PIs just in case might not be a bad idea but that is just my opinion and isn't really based on anything scientific of course.
I wish I had some solid advice but I don't I only have friendship and good wishes to offer so I'm sending you those!!!!!!!!!
I'm so glad for your good news Eureka. I don't know if there is any data out there for extending past 72 or if it even correlates to someone who had HCC not just HCV. I do think perhaps tapering to a maintenance dose to keep things in check while waiting for the PIs just in case might not be a bad idea but that is just my opinion and isn't really based on anything scientific of course.
I wish I had some solid advice but I don't I only have friendship and good wishes to offer so I'm sending you those!!!!!!!!!
It is SUCH a hard call. I've got the end of my 72 coming up in May and it's daunting to lose that safety net, sx and all. I find myself saying maybe just 4 more weeks, maybe eight more weeks, just to make sure.
I've read the less than glowing reports on maintenence therapy, yet my mind tells me that the longer the virus is suppressed the better for the liver, especially if that can be maintained on a lower dose like Willy stated. My stage 4 mind tells me to go for it, My 63 week tx brain says, uh, uh, no way! :-D
I'm happy the CT was clear for HCC. One more hurdle cleared!
Best wishes as always..............Pam
I've read the less than glowing reports on maintenence therapy, yet my mind tells me that the longer the virus is suppressed the better for the liver, especially if that can be maintained on a lower dose like Willy stated. My stage 4 mind tells me to go for it, My 63 week tx brain says, uh, uh, no way! :-D
I'm happy the CT was clear for HCC. One more hurdle cleared!
Best wishes as always..............Pam
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!.
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!.
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.
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.
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.
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.
"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
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
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
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
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.
Be well.
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?
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?
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
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
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.
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.
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
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
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?
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?
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.
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.
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.
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.
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
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
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
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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