Doctors in Barcelona recently reported an unexpected increase in liver cancer recurrence in people who had been or who are being treated for chronic hepatitis C virus (HCV) infection with new potent all-oral medicines called direct acting antivirals (DAAs). All participants had previously been treated for liver cancer. They had been treated successfully with different combinations of DAAs. In their report, the Barcelona doctors focused on patients treated for HCV between October 2014 and December 2015.
We urge our readers to treat this report from Barcelona with caution. The possible association between exposure to DAAs and liver cancer recurrence may be an association that has arisen by chance. Large numbers (tens of thousands) of people in North America and Western Europe have been treated with DAAs and there have not been reports of multiple cases of recurrent liver cancer in such patients by major clinics. The analysis from Barcelona may have been inadvertently biased by its small size and because the researchers included people at very high risk for recurrence of liver cancer.
As all participants had undergone treatment for liver cancer, they subsequently were considered cured and were under routine clinical and laboratory surveillance for the return of liver cancer. For instance, many participants underwent regular CT, MRI (magnetic resonance imaging) and ultrasound scans of their liver every six months.
The Barcelona doctors focused on 58 participants whose average profile was as follows:
- age -- 66 years
- 69% men, 31% women
- 95% had cirrhosis
- 94% were infected with HCV genotype 1b
- the distribution of commonly used anti-HCV regimens included the following: Harvoni (sofosbuvir + ledipasvir) -- 36%; the 3D regimen (Holkira Pak -- dasabuvir + ombitasvir + paritaprevir boosted with ritonavir) -- 26%; sofosbuvir + simeprevir -- 26%; sofosbuvir + daclatasvir -- 10%
The distribution of therapy for the first occurrence of liver cancer was as follows:
- surgery -- 35%
- radiation -- 55%
- injection of chemotherapy into the tumour -- 10%
At the time the Barcelona doctors submitted their report, they noted that 40 participants have been monitored for 12 consecutive weeks after the cessation of DAA therapy. Of these 40 people, 39 (98%) have been cured from HCV.
Here is the situation among the remaining 18 participants:
- three have not yet completed their course of DAAs
- 11 completed their course of DAAs but virological results are not yet available
- three others who completed their course of DAAs have promising preliminary virological results
- one person died due to liver failure
Focus on Liver Cancer After DAA Therapy
Overall, the entire group of 58 participants has been monitored for nearly six months and their current status is as follows:
- 55 participants are alive
- three participants have died
Among the three participants who died, their deaths occurred 12, 10 and five months after DAAs had been initiated.
A total of 15 cases of liver cancer recurrence have been found through CT or MRI scans.
A High Rate and a Theory
The Barcelona doctors claim that the recurrence rate for liver cancer in their report is relatively high, approaching 28%. They do not think that these results are due to tumours being detected very early because of "more intense screening [for liver cancer]." Furthermore, these doctors do not think that DAAs directly caused cancer, as they did not find any evidence for this. Rather, they proposed a complex idea whose key elements are as follows:
- Billions of copies of HCV are produced every day by infected liver cells.
- Once DAA regimens are initiated, HCV levels in the blood quickly become undetectable, sometimes in days or weeks.
- This massive and relatively sudden fall in HCV levels results in the decrease of proteins associated with inflammation also circulating in the blood and immune system. The sudden absence of HCV and inflammatory-associated proteins may somehow impair the immune system's ability to keep liver tumours under monitoring and control.
Readers should note that this idea, though immunologically interesting, has not been proven.
The Barcelona doctors note that reviews of clinical trials of interferon-based therapy for chronic HCV infection have not found any signal of increased risk for liver cancer. That is true, but a meta-analysis of interferon treatment for HCV infection done by researchers at the University of Toronto, reported earlier in this issue of TreatmentUpdate, has found that even among people who were cured there was still a small risk for the subsequent development of liver cancer. Furthermore, a report from Vienna, also in this issue of TreatmentUpdate, notes that cases of liver cancer have occurred among people who were treated with interferon and not DAAs. In that report, about 11% of participants treated with interferon later developed liver cancer.
Some researchers at the University of Palermo in Italy have reviewed the report from Barcelona. They issued this caution: "A definitive estimate of the likelihood of [liver cancer] recurrence is difficult." This difficulty arises because of many factors (that are beyond the scope of our article).
The Barcelona doctors calculated that they found a 28% rate of liver cancer recurrence and they say that this was greater than what they expected. Yet, according to the Italian researchers who reviewed the Barcelona data and then recalculated the estimated risk of liver cancer, the risk of recurrence should have been between 7% and 13%. The Italian researchers therefore see no need for alarm. Note that the numbers of patients upon which both teams used to base their calculations is small and much caution is needed, as these estimates are not robust.
It is possible that the report from Barcelona contains a major flaw: It was inadvertently over-represented with patients who were at very high risk for the recurrence of liver cancer. This could have biased their conclusions.
Whatever the ultimate reason for the apparently increased rate of liver cancer recurrence noted by the Barcelona doctors, their report has ignited disagreement and controversy. To seek clarity on this issue, many people in the liver field will now look to large databases that have data on hundreds, and in some cases thousands, of patients.
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