Interferon and hepatocellular carcinoma

2

3

4

Health Organization DIAMOND Project Group. Diabetologia 1993; 36: 883-92. Bruno G, Merletti F, Vuolo A, Pisu E, Giorio M, Pagano G. Sex differences in incidence of IDDM in age-group 15-29 yr. HIgher risk in males in Province of Turin, Italy. Diabetes Care 1993; 16: 133-36. Muntoni S, Songini M, Sardinian Collaborative Group for Epidemiology of IDDM. High incidence rate of IDDM in Sardinia. Diabetes Care 1992; 15: 1317-22. Bruno G, Merletti F, Pisu E, Pastore G, Marengo C, Pagano G. Incidence of IDDM during 1984-86 in population aged <30 yr residents of Turin, Italy. Diabetes Care 1990; 13: 1051-56.

Interferon and

hepatocellular carcinoma

SiR-Nishiguchi and colleagues (Oct 21, p 1051)’ consider whether interferon (IFN) therapy would be effective in preventing hepatocellular carcinoma (HCC) in patients with cirrhosis secondary to hepatitis C. They randomised 90 patients into one of two groups: (a) IFN for 6 months; or (b) no treatment. The patients were then followed with quarterly laboratory examinations for the appearance of HCC. At the end of follow-up (2-7 years), only two lesions had been found in the treated group, whereas 17 were discovered in the controls. They conclude that IFN reduces the frequency of HCC. Several issues cloud this striking observation. In their introductory comments Nishiguchi and coworkers suggest that the elimination of the virus was the rationale for the use of IFN, but it is difficult to understand the expectation used in their power calculation. They postulate that the therapy would produce an 80% reduction in the rate of HCC development (from an expected frequency of 30% to one of 6%); however, they themselves cite an expected viral clearance rate of 33%. If none of the responders were to develop HCC during follow-up, the frequency in the treated group should still have been at least 20% (since the non-responding two-thirds of the treated group would still produce the cancer at at least the predicted rate). In fact, only seven patients were long-term responders; why was there such a dramatic difference? There are at least two other explanations for these results. First, about half the so-called cancers did not have histological confirmation. Is it possible that some or all of these suspicious lesions were not HCCs? A more important defect in the study relates to the duration of follow-up. Although Nishiguchi and colleagues note that the controls were followed somewhat longer than patients (5-5 vs 4-4 years), a better picture of the difficulty with this follow-up is apparent in their figure 1, in which the numbers of patients available at each point in time are noted. Beginning after the 3rd year, there was an accelerated loss to follow-up of treated patients; from the 4th year on, these differences become highly significant (all p values and usually <0-005 <0-02 [xz-test with Yate’s correction]). When these patients dropped out, the intensive screening ceased and many suspicious lesions would no longer have been observed in the trial. Some might think that if the remaining patients were still representative of the group as a whole, the life-table analysis could still be valid. However, it is likely that there was some systematic reason for the dropouts, and the two subgroups were probably not comparable. Nishiguchi and co-workers are to be commended for undertaking the first long-term trial attempting to assess the usefulness of IFN compared with no treatment in the prevention of important liver disease (rather than merely measuring its effect on surrogate endpoints such as or markers). histological, serological enzymatic, results do the not support the value of viral Unfortunately, elimination; even if there was a reduction in the frequency of HCC, it was not attributable merely to a disappearance of 194

the

virus.

Furthermore,

because

of

the

absence

of

histological confirmation and, even more importantly, because of the disproportionate follow-up, the conclusion may not

even

be

true.

Ronald L Koretz Department of Medicine, Olive View-UCLA

1

Medical

Center, Sylmar, CA 91342, USA

Kuroki T, Nakatani S, et al. Randomised trial of effects of interferon-&agr; on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. Lancet 1995; 346: 1051-55.

Nishiguchi S,

Authors’

reply

SiR-When planning our study, we did not believe that viral eradication was necessary for HCC to be delayed. One longterm study of a Chinese herbal medicine not expected to kill viruses showed about 50% reduction in the frequency of HCC in patients with viral hepatitis.’ In at least 2 years of follow-up of hepatitis B virus (HBV) infection treated with IFN, cancer frequency decreased to zero (no HCC detected in 600 patients), although the virus was not killed.2 Dunk et aP reported that IFN slowed tumour growth and extended mouse survival. In an unpublished study by our group, the number of tumours caused by a carcinogen in mice given IFN was about 20% that in controls. In about 80% of patients with non-A, non-B hepatitis (mostly C), alanine aminotransferase became normal during treatment with IFN (unpublished). This striking improvement, not seen when HBV infection was treated, made us optimistic. Thus, the 80% was a guess, but not a wild one. The one-third we cite in our report was the mean of two studies, and typical of the results of other investigations. The 5-year frequency of 30% that Koretz mentions was calculated from a yearly rate of 6% in patients with cirrhosis,4 and from other Japanese sources.s From our clinical unpublished study we predicted a reduction to 20% of the original, giving 6%. The in the treated group was not "at least 20%" frequency because viral eradication was apparently not necessary for delayed HCC development. We described the procedure used to establish an initial, not final, diagnosis of HCC. Of the 19 cases of suspected HCC, the final diagnosis was based on histological examination in 16 cases. Two other patients have died from HCC (specimens were not obtained) and one patient is alive with advanced disease, with portal invasion detected by ultrasound. Loss to follow-up was not great; all but three surviving patients (one control and two treated patients), who moved, are still visiting hospitals associated with our university. We excluded their data from the analysis because of interlaboratory differences. The groups can still be

compared. Two

reasons

for

drop-out by

treated

patients

were

that,

first, we were recommending that the 38 non-responders to therapy undergo a second course (painful, expensive, and in fact not curative in the six who consented), and second, that in Japan widespread publicity was given in 1994 to suicides have been the outcome of depression caused by IFN treatment. Some non-responders may have perceived the risk of side-effects as being much higher than we did. Viral elimination is not essential for improvement. It is time to discard this disproven idea. However, longer followup may show that development of HCC is merely delayed, not prevented, by IFN. said

to

Tetsuo Kuroki, *Shuhei

Nishiguchi, Shinji Nakatani

Third

Department of Internal Medicine, Osaka City University Medical School, Osaka 545, Japan

1

Oka H, Yamamoto s, Kuroki T,

et

al.

Prospective study of

2

chemoprevention of hepatocellular carcinoma with Sho-saiko-to (TJ-9). Cancer 1995; 76: 743-49. Oon C-J. Long-term survival following treatment of hepatocellular carcinoma in Singapore: evaluation of Welferon in the prophylaxis of high-risk pre-cancerous conditions. Cancer Chemother Pharmacol 1992;

31: S137-42. Dunk AA, Ikeda T, Pignatelli M, Thomas HC. Human lymphoblastoid interferon in vitro and in vivo studies in hepatocellular carcinoma.J Hepatol 1986; 2: 419-29. 4 Oka H, Kurioka N, Kim K, et al. Prospective study of early detection of hepatocellular carcinoma in patients with cirrhosis. Hepatology 1990; 12: 680-87. 5 Muto Y, Moriwaki H, Shimazaki M, et al. High risk group of hepatocellular carcinoma in man, with special reference to its clinical significance for the screening of early liver cancer. Nippon Shokakibyo Gakkai Zasshi 1989; 86: 2833-38 (in Japanese). 3

SiR-Nishiguchi and colleagues’ report a reduced incidence of hepatocellular carcinoma (HCC) in HCV-positive cirrhosis given IFN-a. From October, 1990, to May, 1995, we treated 84 patients with type C cirrhosis belonging to Child-Pugh class A with IFN-a for 1 year. by November, 1995, the median observation period was 30 months (range 5-62). Before treatment, HCC was excluded by ultrasonography, which was then repeated every 6 months. HCC appearance was diagnosed by ultrasonography and hepatic arteriography with Lipiodol followed by computed tomographic scan. Baseline characteristics of our patients were close to those of Nishiguchi et al. The mean cumulative IFN-a, dose we gave was higher than or similar to that used in their study (461 vs 216 or 432 MIU). 27 patients (32%) in our study and six of 45 (13%) in the Japanese investigation received a second IFN-a course (p=0-015); five of our patients received a third course. Similarly to Nishiguchi’s results, alanine aminotransferase (ALT) was normal in 26% (22) of patients at the end of therapy and in 20% (17) after follow-up. HCC developed in nine patients (11%) within 7-45 months (figure), the cumulative rate of tumour-free 5-year survival being 80%. Interestingly, HCC appeared in four of nine patients with a temporary response and two of nine with a sustained response. HCC developed in two patients during the third IFN-a course. The HCC yearly occurrence rates were 4%, 3%, 4%, 10%, and 0, and are in accord with those in non-treated Caucasian2-4 and Italian cirrhotic patients.4 In sharp contrast, Nishiguchi and colleagues detected HCCs in two (4%) treated patients, neither in the first 3 years of follow-up. Although different race and geographic area might account for these discrepant results, possible biases should be considered. First, treated patients were younger than untreated patients (p=0056, t-test), and age could be important, since HCC incidence is age dependent’

sharply in the sixth decide.5 Second, in some cases (not specified) liver scintigraphy alone was used. In view of the low sensitivity of this technique, some HCC may have been missed. Third, after the 4th year of follow-up, the number of treated patients at risk declined compared with untreated. This finding may result from shorter follow-up or drop-outs, leading to underestimated HCC incidence. and increases

*Pietro Andreone, Carmela Cursaro, Annagiulia Gramenzi, Franco Trevisani, Giovanni Gasbarrini, Mauro Bernardi *Patologia Medica I, University of Bologna, 40138 Bologna, Italy; and Clinica Medica, Catholic

1

2

3

4

5

University,

Rome

Kuroki T, Nakatani S, et al. Randomised trial of effects of interferon-&agr; an incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. Lancet 1995; 346: 1051-55. Cottone M, Turri M, Caltagirone M, et al. Screening for hepatocellular carcinoma in patients with Child’s A cirrhosis: an 18year prospective study by ultrasound and alphafetoprotein. J Hepatol 1994; 21: 1029-34. Pateron D, Ganne N, Trinchet JC, et al. Prospective study of screening for hepatocellular carcinoma in Caucasian patients with cirrhosis. J Hepatol 1994; 20: 65-71. Colombo M, De Franchis R, Del Ninno E, et al. Hepatocellular carcinoma in Italian patients with cirrhosis. N Engl J Med 1991; 325: 675-80. Trevisani F, D’Intino PE, Caraceni C, et al. Etiologic factors and clinical presentation of hepatocellular carcinoma. Cancer 1995; 75: 2220-32.

Nishiguchi S,

UK adults’ risk from

eating beef

SIR-The

amount of bovine spongiform encephalopathy (BSE) infectivity present in beef has been assayed in mice and found to be low, but the sensitivity of this assay is unknown. Inadequate data are available to predict the amount required to infect human beings-current

calculations as to the size of the human risk have been made with experimental data from transmissible spongiform encephalopathies (TSEs) of other species.’ The annual rate of BSE in affected herds has changed little since the beginning of the epidemic2 and the rise in incidence was largely due to the increase in the number of herds affected. By 1993/94, over 85% of UK dairy cattle were in a BSE-affected herd. Although some of the reported fall since then may be due to a change in the proportion of cases reaching official statistics3 the annual amount of BSE infectivity present in the UK adult human diet could not be increasing. Because of this, and as the risk from it may be related to the logarithm of the cumulative dose, it is possible that most of the risk from BSE had already been taken. Data were calculated from Ministry of Agriculture, Fisheries, and Food (MAFF) statistics by published techniques.3 BSE case numbers and the proportion of incubation period at slaughter were calculated assuming that all cases with symptoms were reported to the veterinary officer (VO), all BSE cases were accepted by the VO, all slaughtered, all diagnosed with 100% sensitive methods before 1992 (and in 1994), and that no BSE will appear in cattle born after 1991. Case numbers in 1989, 1992, and 1993 were calculated similarly but were statistically corrected for data not reaching MAFF. Murine assay was taken to indicate that bovine tissues eaten by humans contains less than 106 IU/g. Humans were assumed to have eaten since 1980 only liver, kidney, muscle, and the peripheral nerves within. !,3 Dietary distribution within the population of various tissues is calculated as previously.’ Oral doses of BSE are considered to be cumulative because no immunity is formed to TSEs and aspects of infection are advanced by increased doses.4 The figure shows the 195