Surviving Hepatits C-Related HCC and Cirrhosis

[eureka254]

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

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

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

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

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

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

[eureka254]

I 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

[willing]

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.

[eureka254]

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

[HectorSF]

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

[willing]

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

[Marcia2202]

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.