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Interferon in Wonderland
October 1998
SELECTED SUMMARIES
In 1989, Lamberts et al. (Lancet 1989;1:242–244, N Engl J Med 1990;323:1246–1249) developed a technique that allowed in vivo visualization of tumors in humans after intravenous administration of 123I coupled to octreotide and was able to detect primary tumors or metastases in 12 of 13 patients with carcinoids and 7 of 9 patients with pancreatic neuroendocrine tumors. Although promising, this technique was hampered by the difficulty in preparing pure 123I, by the short half-life of the radionuclide, and by hepatobiliary clearance of the radiolabeled peptide, which created a high background of abdominal radioactivity and made localization of small tumors difficult (Gastroenterology 1993;105:1909–1914). These limitations have been overcome by the development of 111In-DTPA–labeled somatostatin analogues, which are easier to prepare, have longer half-lives, and are excreted primarily by the kidneys (Life Sci 1991;49:1593–1601, Semin Oncol 1994;21[Suppl 13]:6–14). Using 111In-DTPA-D-PHE1-octreotide in 40 patients with immunohistologically proven gastroenteropancreatic neuroendocrine tumors, mostly carcinoids, Scheru¨bl et al. (Gastroenterology 1993;105:1705–1709) reported successful visualization of the tumors in 80% of patients; in 16 of 40 patients (40%) additional tumors were localized that were not detected by ultrasonography, CT scanning, or magnetic resonance imaging. In the European Multicenter Trial (Nucl Med Annu 1995:1–50), SRS visualized 297 of 388 (77%) known sites and revealed another 166 unsuspected lesions in 308 patients (54%); 40% of these unsuspected lesions were subsequently confirmed as true positives based on the results of additional imaging procedures or histology obtained during the follow-up period. In the present study by Lebtahi et al., which included 160 patients, almost half with gastrinoma, SRS was confirmed to be accurate, visualizing 84% of 196 tumor sites detected by conventional imaging and discovering 111 unsuspected new tumor sites in 50% of the patients. Although the demonstration of additional tumor sites is unlikely to alter the management of patients with known metastases, it carries critical clinical relevance for the management of patients with a single known lesion or without any known lesion because it may obviate the need for surgery or alter the type of surgery performed. In the present study, therapeutic management was altered in 25% of the patients due to the discovery of unsuspected liver tumors in 7 patients, contralateral liver tumors before hepatectomy in 2 patients, and extrahepatic metastases in 31 patients. SRS with 111In-DTPA-PHE1-octreotide, also known as 111Inpenetreotide and commercially available as Octreoscan (Mallinckrodt Medical, Petten, The Netherlands, and St. Louis, MO), has come of age as a safe and accurate first-line imaging modality for localizing and determining the extent of spread of gastroenteropancreatic neuroendocrine tumors. The cost and radiation exposure are similar to that of a CT scan of the chest, yet SRS images the entire body, is relatively easy to interpret, has a high power of resolution for tumors as small as 1 cm, and detects tumors unsuspected by CT in 40%–60% of patients. Accurate staging by SRS impacts on the choice of therapy (surgery with curative or palliative intent, medical treatment with somatostatin analogues, hepatic artery embolization, or systemic chemotherapy) offered to the patient. For tumors in the duodenopancreatic area, EUS may be a valuable adjunct; a combination of EUS and SRS detected 90% of primary neuroendocrine tumors in the present study. MITCHELL L. SCHUBERT, M.D.
Reply. Several studies have now shown that Octreoscan scintigraphy is the first-line imaging modality for the detection of endocrine tumors. It evaluates the spread of the disease, and its results alter management in many patients (J Nucl Med 1995;36:542–549, Gut
1027
1997;41:107–114, Gastroenterology 1997;112:335–347, J Nucl Med 1997;38:853–858). The ability of Octreoscan to alter management varies according to the clinical setting. In patients without metastases, in whom the goals of imaging are to detect unknown liver metastases and to find the primary tumor, Octreoscan is the first-line technique. It is the most sensitive imaging modality to detect liver metastases (Ann Intern Med 1996;125:26–34), and its negative predictive value is very high (Radiology 1997;202:151–158). Although its sensitivity for the detection of primary tumor is not as high as for the detection of liver metastases, Octreoscan is often the only imaging technique that visualizes midgut carcinoids (Surgery 1994;116:1112–1122). Ninety percent of duodenopancreatic tumors, especially gastrinoma, are detected by the combination of Octreoscan and EUS (Gastroenterology 1996;111:845–854). In patients with advanced disease, Octreoscan can detect metastases that would contraindicate curative liver surgery or local treatment such as liver embolization. Finally, Octreoscan can identify multiple endocrine neoplasia type 1–related tumors, especialy in the chest (Gut 1997;41:107–114). R. LEBTAHI G. CADIOT M. MIGNON D. LE GULUDEC
INTERFERON IN WONDERLAND Bennett WG, Inoue Y, Beck JR, Wong JB, Pauker SG, Davis GL (University of Florida College of Medicine, Gainesville, Florida; Baylor College of Medicine, Houston, Texas; Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan; and New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts). Estimates of the costeffectiveness of a single course of interferon-a-2b in patients with histologically mild chronic hepatitis C. Ann Intern Med 1997;127:855–865. Noting that there are 3.9 million people chronically infected with the hepatitis C virus (HCV) and that 8300 deaths and 730 additional liver transplantations occur annually as a consequence, Bennett et al. performed a decision analysis to attempt to assess the impact that interferon (IFN) treatment might have on the long-term course and costs of this infection in the subgroup of patients having histologically mild chronic disease. Using data from the literature, they created a model predicting the long-term course of the disease. Employing data from five prospective randomized controlled trials of IFN (and the individual patient databases provided by Schering-Plough, the sponsor of those trials), they calculated that 27% of patients with mild or moderate chronic hepatitis would have a desirable long-term response (i.e., become seronegative for markers of active HCV infection). As is the case in all such analyses, the authors had to make assumptions when actual data were not available. They assumed that patients who lose HCV would not develop progressive liver disease. They also apparently assumed that the course of the disease in nonresponders was the same as in those who had never been treated. To make some of their cost comparisons, they asked a panel of hepatologists to make quality-of-life adjustments for various states of disease. (These
1028
SELECTED SUMMARIES
experts decided that a year of mild chronic hepatitis was only worth 0.82 years of perfect health, a year of compensated cirrhosis was only worth 0.70 years of perfect health, and that a year of being treated with IFN was only worth 0.93 years of perfect health.) The investigators did perform sensitivity analyses to test the extreme values of their various estimates. Included in this latter calculation was an attempt to address the issue that IFN responses only occurred in individuals destined to become HCV negative anyway by increasing the annual rate of spontaneous seroconversion from 0.2% to 6.2% (so that, after 5 years, 27% would be seronegative). Part of the funding for this study came from ScheringPlough (an unrestricted grant). The investigators stated that the company had no input into any component of the study (from inception to publication) except to facilitate access to the databases, and that none of them had any relationship with the company that would represent a conflict of interest. The model predicted that IFN would increase the average life expectancy by times ranging from 22 days (if begun at age 70) to 3.1 years (if begun at age 20). In the base case scenario (35-year-old man), the discounted marginal cost-effective ratio was $1900 for each life-year gained. For a 20- or 70-year old, these figures were $530 and $62,000 respectively. When the higher rate of spontaneous clearance was used, life expectancy still increased (0.3 year in the base case). The investigators concluded that IFN would prolong life expectancy at a reasonable marginal cost per year of life gained, particularly in younger patients. Kim WR, Poterucha JJ, Hermans JE, Therneau TM, Dickson ER, Evans RW, Gross JB (Division of Gastroenterology and Hepatology and Section of Biostatistics and Health Services Evaluation, Mayo Clinic, Rochester, Minnesota). Cost-effectiveness of 6 and 12 months of interferon-a therapy for chronic hepatitis C. Ann Intern Med 1997;127:866–874. Kim et al. also noted that the HCV is a major cause of liver-related illness in the United States. They cited a report that from 35,000 to 180,000 persons become infected every year (70% moving on to chronic infection) and that more than 8000 die of HCV-related disease annually. They performed a decision analysis to assess the effect of IFN treatment in all patients with chronic hepatitis C. They modeled two different therapeutic interventions, a 6-month course and a 12-month one. These investigators also used data from the literature to create the natural history models as well as to predict IFN responses. To deal with the possibility that IFN responders were less likely to develop end-stage liver disease, this model included two types of patients: those with aggressive disease that progressed rapidly from chronic hepatitis to compensated cirrhosis (10% per year) and those with indolent disease (progressing at 1% per year). The patients with indolent disease were postulated to be more likely to have an IFN response (20% and 30% after 6 and 12 months) than those with aggressive disease (2% and 3%, respectively). This model
GASTROENTEROLOGY Vol. 115, No. 4
also assumed that the nonresponders would have the same natural history as did those who were not treated. Qualityadjusted life years were estimated by a panel of hepatologists; in this case, a year with chronic hepatitis was worth 0.95 years of perfect health. The analysis suggested that IFN would prolong life expectancy; the absolute risk of dying of liver disease was decreased by 1.5% with a 6-month course and by 2.2% with a 12-month one. On average, the two treatment regimens added 0.25 and 0.37 quality-adjusted life years. The cost for one such year ranged from $1100 (6 months of therapy in a 30-year-old) to $12,800 (12 months of treatment in a 60-year-old). The respective costs for each liver death prevented was $17,500 and $288,900. The authors concluded that the cost of IFN therapy is justifiable for all patients with chronic hepatitis C except perhaps for those older than 60. Comment.
‘‘No, no! Sentence first—verdict afterward.’’ —Queen of Hearts in Alice in Wonderland
Presently we have no data from prospective randomized controlled trials that IFN prevents any patient from developing end-stage liver disease. Such a trial would have to enroll hundreds of patients and would take one or more decades to perform. Bennett et al. and Kim et al. are attempting to fill this void in our data base with information derived more indirectly, namely, from mathematical models. Decision analysis has its best applicability when all of the data are known, and the method is being used simply to compare the costs and benefits of various interventions. The more assumptions that must be made, the weaker are the conclusions. How does this relate to IFN and hepatitis C? Most patients who are infected with HCV are not going to have liver trouble during their lifetimes. One way to look at this issue of progression is to calculate a ‘‘latent phase,’’ the average time that elapses from the moment of infection to the occurrence of organ death. This is done by dividing the prevalence of the disease by its incidence. Bennett et al. noted that there are currently 3.9 million infected people in the United States, and that hepatitis C is responsible for 8300 deaths and 730 transplantations. The latent phase is 3,900,000 divided by 9030, or 432 years! From the epidemiological data quoted by Kim et al., one can calculate that from 24,000 to 126,000 cases of chronic hepatitis C arise each year, but only 8000 of these people die. This suggests that only 7%–33% of patients with chronic hepatitis C will have a fatal liver disease. (Neither of these epidemiological calculations considers the confounding role of alcohol abuse as a cofactor in the development of cirrhosis.) Both of these calculations do assume that a steady-state exists. There has been some concern that we are on the brink of a large upswing in HCV-related liver failure as people who were infected in the 1960s and 1970s grow older. This concern is only a hypothesis; interestingly, the mortality rate from liver disease actually declined from 1980 to 1989 (13.5/100,000 to 10.5/100,000), a drop that could not be accounted for simply by an increase in liver transplantation (MMWR 1993;41:969–973). The authors of both decision analyses assumed that the important outcome in IFN therapy is the biochemical and serological response. Only a minority of treated patients will have such a response. The question that decision analysis cannot answer is whether the minority of patients who have this response is the same as the minority of patients who ultimately develop end-stage liver disease. If these two
October 1998
SELECTED SUMMARIES
groups are independent, the responders are all people who would never have had liver trouble even if they had never been exposed to IFN. (This phenomenon, rather than a therapeutic effect of IFN, may also account for the observations that IFN responders have good prognoses [Gastroenterology 1997;112:1418–1420, Ann Intern Med 1997;127: 875–881].) Furthermore, the treatment would have no effect on the subgroup destined to get into trouble. We know that responders are individuals who have shorter durations of infection, lower titers of HCV RNA, and no histological evidence of cirrhosis. If such patients are removed from a population that is being treated, the residual individuals are going to be more likely to have these adverse prognostic markers, and their natural histories are likely to be worse on average than would those composing the original untreated group. While both analyses attempted to deal with these unknowns, the sensitivity analyses did not evaluate the true worst-case scenario. Bennett et al. considered the possibility that response would only occur in those destined to become seronegative eventually. Kim et al. attempted to deal with the issue by confining IFN responses to the subgroup with more slowly progressive disease. Efficacy remained because both models still resulted in some responders otherwise getting into trouble. (The worst-case scenario is that none of the responders were ever at risk of developing end-stage liver disease.) This bias is further compounded by underestimating the rate of progression in the nonresponders (by assuming that that rate is the same as that of an untreated group). A word should also be noted about the quality-of-life adjustments. The quantitations were established by hepatologists, and such estimates can reflect the values of physicians rather than patients. For instance, the panel employed by Bennett et al. believed that a year with mild chronic hepatitis or a year of compensated cirrhosis, both largely asymptomatic conditions, were only worth 0.83 and 0.70 healthy years, but a year of IFN treatment (with its attendant symptoms) was worth 0.92 healthy years. Is it true that the anxiety over developing end-stage liver disease (which is largely instilled by the physician anyway) is worse than having real symptoms, or is this judgment simply a reflection of the experts’ anxiety about abnormal tests? Because we have no direct evidence of IFN efficacy, we cannot use decision analysis methodology to calculate costs and benefits. Other plausible assumptions would have led to a conclusion that no efficacy exists (in which case there is no benefit to which to ascribe a cost). As discomforting as it may appear, the only way we will know if IFN (or any other agent that relies on the same intermediate end points) should be used is to perform the large, lengthy trial. Outside of Wonderland, the verdict (data from randomized trials) must come before the sentence (decision regarding use). RONALD L. KORETZ, M.D.
Reply. We have reviewed the provocative comments from Dr. Koretz. Our effectiveness analysis was based on data obtained from treatment trials in which short-term efficacy of IFN was demonstrated
1029
in alleviating biochemical, histological, and viral signs of hepatitis. Our model was specifically designed to allow for the possibility that patients who respond to IFN are likely to have indolent disease, whereas nonresponders are much more likely to have progressive disease. In addition, the limitations of decision analysis were discussed in the article. Dr. Koretz’s hypothesis is that no patient responding to IFN would have had progressive liver disease. While this hypothesis cannot be disproved, there is indirect evidence to the contrary. For example, in studies in which liver histology was followed longitudinally in patients with chronic hepatitis C, a substantial number of subjects with mild chronic hepatitis were found to progress to more advanced stages of liver disease (Gut 1993;513–516). More advanced liver disease has been associated with longer duration of infection with hepatitis C (Intervirology 1994;37:101–107). Furthermore, complete regression of histological lesions of hepatitis does occur in sustained responders (Ann Intern Med 1997;127:875–881). Thus, it appears likely that seemingly mild disease may progress in some patients, and that a sustained response to IFN may halt further progression of liver disease. Quality of life in patients with chronic hepatitis C should also be considered in assessing the benefits of IFN (Hepatology 1997;26: 422A). Patients with chronic hepatitis C may have diminished quality of life, independent of the degree of hepatic inflammation, or the mode of acquisition of the infection (Hepatology 1998;27:209–212). In our computation of quality-adjusted life years (QALY), 56% of the gain in QALYs with IFN treatment was attributed to the improvement in the quality of life of patients in the chronic hepatitis and compensated cirrhosis states, rather than prolongation of survival. Because patients often spend the most time in these two states, even a small improvement in their perceived quality of life becomes very significant when accumulated over a lifetime. As was clearly stated in our article, the objective of decision analytic models is not to create data where there are none. Instead, models such as ours put available data into perspective, based on actual estimates and realistic assumptions, so that they can be used to better inform clinical decision making. In this context, the strength of decision analysis lies in its ability to allow us to incorporate the results of sensitivity analyses taking into consideration a range of estimates of important variables. As Dr. Koretz proposes, what constitutes a reasonable range of estimates may be a matter of debate. In our opinion, however, withholding potentially beneficial treatment because of a lack of long-term outcome data may not be justified. W. RAY KIM JOHN J. POTERUCHA JOHN E. HERMANS TERRY M. THERNEAU E. ROLLAND DICKSON ROGER W. EVANS JOHN B. GROSS, Jr.
SELECTED SUMMARIES
In 1989, Lamberts et al. (Lancet 1989;1:242–244, N Engl J Med 1990;323:1246–1249) developed a technique that allowed in vivo visualization of tumors in humans after intravenous administration of 123I coupled to octreotide and was able to detect primary tumors or metastases in 12 of 13 patients with carcinoids and 7 of 9 patients with pancreatic neuroendocrine tumors. Although promising, this technique was hampered by the difficulty in preparing pure 123I, by the short half-life of the radionuclide, and by hepatobiliary clearance of the radiolabeled peptide, which created a high background of abdominal radioactivity and made localization of small tumors difficult (Gastroenterology 1993;105:1909–1914). These limitations have been overcome by the development of 111In-DTPA–labeled somatostatin analogues, which are easier to prepare, have longer half-lives, and are excreted primarily by the kidneys (Life Sci 1991;49:1593–1601, Semin Oncol 1994;21[Suppl 13]:6–14). Using 111In-DTPA-D-PHE1-octreotide in 40 patients with immunohistologically proven gastroenteropancreatic neuroendocrine tumors, mostly carcinoids, Scheru¨bl et al. (Gastroenterology 1993;105:1705–1709) reported successful visualization of the tumors in 80% of patients; in 16 of 40 patients (40%) additional tumors were localized that were not detected by ultrasonography, CT scanning, or magnetic resonance imaging. In the European Multicenter Trial (Nucl Med Annu 1995:1–50), SRS visualized 297 of 388 (77%) known sites and revealed another 166 unsuspected lesions in 308 patients (54%); 40% of these unsuspected lesions were subsequently confirmed as true positives based on the results of additional imaging procedures or histology obtained during the follow-up period. In the present study by Lebtahi et al., which included 160 patients, almost half with gastrinoma, SRS was confirmed to be accurate, visualizing 84% of 196 tumor sites detected by conventional imaging and discovering 111 unsuspected new tumor sites in 50% of the patients. Although the demonstration of additional tumor sites is unlikely to alter the management of patients with known metastases, it carries critical clinical relevance for the management of patients with a single known lesion or without any known lesion because it may obviate the need for surgery or alter the type of surgery performed. In the present study, therapeutic management was altered in 25% of the patients due to the discovery of unsuspected liver tumors in 7 patients, contralateral liver tumors before hepatectomy in 2 patients, and extrahepatic metastases in 31 patients. SRS with 111In-DTPA-PHE1-octreotide, also known as 111Inpenetreotide and commercially available as Octreoscan (Mallinckrodt Medical, Petten, The Netherlands, and St. Louis, MO), has come of age as a safe and accurate first-line imaging modality for localizing and determining the extent of spread of gastroenteropancreatic neuroendocrine tumors. The cost and radiation exposure are similar to that of a CT scan of the chest, yet SRS images the entire body, is relatively easy to interpret, has a high power of resolution for tumors as small as 1 cm, and detects tumors unsuspected by CT in 40%–60% of patients. Accurate staging by SRS impacts on the choice of therapy (surgery with curative or palliative intent, medical treatment with somatostatin analogues, hepatic artery embolization, or systemic chemotherapy) offered to the patient. For tumors in the duodenopancreatic area, EUS may be a valuable adjunct; a combination of EUS and SRS detected 90% of primary neuroendocrine tumors in the present study. MITCHELL L. SCHUBERT, M.D.
Reply. Several studies have now shown that Octreoscan scintigraphy is the first-line imaging modality for the detection of endocrine tumors. It evaluates the spread of the disease, and its results alter management in many patients (J Nucl Med 1995;36:542–549, Gut
1027
1997;41:107–114, Gastroenterology 1997;112:335–347, J Nucl Med 1997;38:853–858). The ability of Octreoscan to alter management varies according to the clinical setting. In patients without metastases, in whom the goals of imaging are to detect unknown liver metastases and to find the primary tumor, Octreoscan is the first-line technique. It is the most sensitive imaging modality to detect liver metastases (Ann Intern Med 1996;125:26–34), and its negative predictive value is very high (Radiology 1997;202:151–158). Although its sensitivity for the detection of primary tumor is not as high as for the detection of liver metastases, Octreoscan is often the only imaging technique that visualizes midgut carcinoids (Surgery 1994;116:1112–1122). Ninety percent of duodenopancreatic tumors, especially gastrinoma, are detected by the combination of Octreoscan and EUS (Gastroenterology 1996;111:845–854). In patients with advanced disease, Octreoscan can detect metastases that would contraindicate curative liver surgery or local treatment such as liver embolization. Finally, Octreoscan can identify multiple endocrine neoplasia type 1–related tumors, especialy in the chest (Gut 1997;41:107–114). R. LEBTAHI G. CADIOT M. MIGNON D. LE GULUDEC
INTERFERON IN WONDERLAND Bennett WG, Inoue Y, Beck JR, Wong JB, Pauker SG, Davis GL (University of Florida College of Medicine, Gainesville, Florida; Baylor College of Medicine, Houston, Texas; Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan; and New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts). Estimates of the costeffectiveness of a single course of interferon-a-2b in patients with histologically mild chronic hepatitis C. Ann Intern Med 1997;127:855–865. Noting that there are 3.9 million people chronically infected with the hepatitis C virus (HCV) and that 8300 deaths and 730 additional liver transplantations occur annually as a consequence, Bennett et al. performed a decision analysis to attempt to assess the impact that interferon (IFN) treatment might have on the long-term course and costs of this infection in the subgroup of patients having histologically mild chronic disease. Using data from the literature, they created a model predicting the long-term course of the disease. Employing data from five prospective randomized controlled trials of IFN (and the individual patient databases provided by Schering-Plough, the sponsor of those trials), they calculated that 27% of patients with mild or moderate chronic hepatitis would have a desirable long-term response (i.e., become seronegative for markers of active HCV infection). As is the case in all such analyses, the authors had to make assumptions when actual data were not available. They assumed that patients who lose HCV would not develop progressive liver disease. They also apparently assumed that the course of the disease in nonresponders was the same as in those who had never been treated. To make some of their cost comparisons, they asked a panel of hepatologists to make quality-of-life adjustments for various states of disease. (These
1028
SELECTED SUMMARIES
experts decided that a year of mild chronic hepatitis was only worth 0.82 years of perfect health, a year of compensated cirrhosis was only worth 0.70 years of perfect health, and that a year of being treated with IFN was only worth 0.93 years of perfect health.) The investigators did perform sensitivity analyses to test the extreme values of their various estimates. Included in this latter calculation was an attempt to address the issue that IFN responses only occurred in individuals destined to become HCV negative anyway by increasing the annual rate of spontaneous seroconversion from 0.2% to 6.2% (so that, after 5 years, 27% would be seronegative). Part of the funding for this study came from ScheringPlough (an unrestricted grant). The investigators stated that the company had no input into any component of the study (from inception to publication) except to facilitate access to the databases, and that none of them had any relationship with the company that would represent a conflict of interest. The model predicted that IFN would increase the average life expectancy by times ranging from 22 days (if begun at age 70) to 3.1 years (if begun at age 20). In the base case scenario (35-year-old man), the discounted marginal cost-effective ratio was $1900 for each life-year gained. For a 20- or 70-year old, these figures were $530 and $62,000 respectively. When the higher rate of spontaneous clearance was used, life expectancy still increased (0.3 year in the base case). The investigators concluded that IFN would prolong life expectancy at a reasonable marginal cost per year of life gained, particularly in younger patients. Kim WR, Poterucha JJ, Hermans JE, Therneau TM, Dickson ER, Evans RW, Gross JB (Division of Gastroenterology and Hepatology and Section of Biostatistics and Health Services Evaluation, Mayo Clinic, Rochester, Minnesota). Cost-effectiveness of 6 and 12 months of interferon-a therapy for chronic hepatitis C. Ann Intern Med 1997;127:866–874. Kim et al. also noted that the HCV is a major cause of liver-related illness in the United States. They cited a report that from 35,000 to 180,000 persons become infected every year (70% moving on to chronic infection) and that more than 8000 die of HCV-related disease annually. They performed a decision analysis to assess the effect of IFN treatment in all patients with chronic hepatitis C. They modeled two different therapeutic interventions, a 6-month course and a 12-month one. These investigators also used data from the literature to create the natural history models as well as to predict IFN responses. To deal with the possibility that IFN responders were less likely to develop end-stage liver disease, this model included two types of patients: those with aggressive disease that progressed rapidly from chronic hepatitis to compensated cirrhosis (10% per year) and those with indolent disease (progressing at 1% per year). The patients with indolent disease were postulated to be more likely to have an IFN response (20% and 30% after 6 and 12 months) than those with aggressive disease (2% and 3%, respectively). This model
GASTROENTEROLOGY Vol. 115, No. 4
also assumed that the nonresponders would have the same natural history as did those who were not treated. Qualityadjusted life years were estimated by a panel of hepatologists; in this case, a year with chronic hepatitis was worth 0.95 years of perfect health. The analysis suggested that IFN would prolong life expectancy; the absolute risk of dying of liver disease was decreased by 1.5% with a 6-month course and by 2.2% with a 12-month one. On average, the two treatment regimens added 0.25 and 0.37 quality-adjusted life years. The cost for one such year ranged from $1100 (6 months of therapy in a 30-year-old) to $12,800 (12 months of treatment in a 60-year-old). The respective costs for each liver death prevented was $17,500 and $288,900. The authors concluded that the cost of IFN therapy is justifiable for all patients with chronic hepatitis C except perhaps for those older than 60. Comment.
‘‘No, no! Sentence first—verdict afterward.’’ —Queen of Hearts in Alice in Wonderland
Presently we have no data from prospective randomized controlled trials that IFN prevents any patient from developing end-stage liver disease. Such a trial would have to enroll hundreds of patients and would take one or more decades to perform. Bennett et al. and Kim et al. are attempting to fill this void in our data base with information derived more indirectly, namely, from mathematical models. Decision analysis has its best applicability when all of the data are known, and the method is being used simply to compare the costs and benefits of various interventions. The more assumptions that must be made, the weaker are the conclusions. How does this relate to IFN and hepatitis C? Most patients who are infected with HCV are not going to have liver trouble during their lifetimes. One way to look at this issue of progression is to calculate a ‘‘latent phase,’’ the average time that elapses from the moment of infection to the occurrence of organ death. This is done by dividing the prevalence of the disease by its incidence. Bennett et al. noted that there are currently 3.9 million infected people in the United States, and that hepatitis C is responsible for 8300 deaths and 730 transplantations. The latent phase is 3,900,000 divided by 9030, or 432 years! From the epidemiological data quoted by Kim et al., one can calculate that from 24,000 to 126,000 cases of chronic hepatitis C arise each year, but only 8000 of these people die. This suggests that only 7%–33% of patients with chronic hepatitis C will have a fatal liver disease. (Neither of these epidemiological calculations considers the confounding role of alcohol abuse as a cofactor in the development of cirrhosis.) Both of these calculations do assume that a steady-state exists. There has been some concern that we are on the brink of a large upswing in HCV-related liver failure as people who were infected in the 1960s and 1970s grow older. This concern is only a hypothesis; interestingly, the mortality rate from liver disease actually declined from 1980 to 1989 (13.5/100,000 to 10.5/100,000), a drop that could not be accounted for simply by an increase in liver transplantation (MMWR 1993;41:969–973). The authors of both decision analyses assumed that the important outcome in IFN therapy is the biochemical and serological response. Only a minority of treated patients will have such a response. The question that decision analysis cannot answer is whether the minority of patients who have this response is the same as the minority of patients who ultimately develop end-stage liver disease. If these two
October 1998
SELECTED SUMMARIES
groups are independent, the responders are all people who would never have had liver trouble even if they had never been exposed to IFN. (This phenomenon, rather than a therapeutic effect of IFN, may also account for the observations that IFN responders have good prognoses [Gastroenterology 1997;112:1418–1420, Ann Intern Med 1997;127: 875–881].) Furthermore, the treatment would have no effect on the subgroup destined to get into trouble. We know that responders are individuals who have shorter durations of infection, lower titers of HCV RNA, and no histological evidence of cirrhosis. If such patients are removed from a population that is being treated, the residual individuals are going to be more likely to have these adverse prognostic markers, and their natural histories are likely to be worse on average than would those composing the original untreated group. While both analyses attempted to deal with these unknowns, the sensitivity analyses did not evaluate the true worst-case scenario. Bennett et al. considered the possibility that response would only occur in those destined to become seronegative eventually. Kim et al. attempted to deal with the issue by confining IFN responses to the subgroup with more slowly progressive disease. Efficacy remained because both models still resulted in some responders otherwise getting into trouble. (The worst-case scenario is that none of the responders were ever at risk of developing end-stage liver disease.) This bias is further compounded by underestimating the rate of progression in the nonresponders (by assuming that that rate is the same as that of an untreated group). A word should also be noted about the quality-of-life adjustments. The quantitations were established by hepatologists, and such estimates can reflect the values of physicians rather than patients. For instance, the panel employed by Bennett et al. believed that a year with mild chronic hepatitis or a year of compensated cirrhosis, both largely asymptomatic conditions, were only worth 0.83 and 0.70 healthy years, but a year of IFN treatment (with its attendant symptoms) was worth 0.92 healthy years. Is it true that the anxiety over developing end-stage liver disease (which is largely instilled by the physician anyway) is worse than having real symptoms, or is this judgment simply a reflection of the experts’ anxiety about abnormal tests? Because we have no direct evidence of IFN efficacy, we cannot use decision analysis methodology to calculate costs and benefits. Other plausible assumptions would have led to a conclusion that no efficacy exists (in which case there is no benefit to which to ascribe a cost). As discomforting as it may appear, the only way we will know if IFN (or any other agent that relies on the same intermediate end points) should be used is to perform the large, lengthy trial. Outside of Wonderland, the verdict (data from randomized trials) must come before the sentence (decision regarding use). RONALD L. KORETZ, M.D.
Reply. We have reviewed the provocative comments from Dr. Koretz. Our effectiveness analysis was based on data obtained from treatment trials in which short-term efficacy of IFN was demonstrated
1029
in alleviating biochemical, histological, and viral signs of hepatitis. Our model was specifically designed to allow for the possibility that patients who respond to IFN are likely to have indolent disease, whereas nonresponders are much more likely to have progressive disease. In addition, the limitations of decision analysis were discussed in the article. Dr. Koretz’s hypothesis is that no patient responding to IFN would have had progressive liver disease. While this hypothesis cannot be disproved, there is indirect evidence to the contrary. For example, in studies in which liver histology was followed longitudinally in patients with chronic hepatitis C, a substantial number of subjects with mild chronic hepatitis were found to progress to more advanced stages of liver disease (Gut 1993;513–516). More advanced liver disease has been associated with longer duration of infection with hepatitis C (Intervirology 1994;37:101–107). Furthermore, complete regression of histological lesions of hepatitis does occur in sustained responders (Ann Intern Med 1997;127:875–881). Thus, it appears likely that seemingly mild disease may progress in some patients, and that a sustained response to IFN may halt further progression of liver disease. Quality of life in patients with chronic hepatitis C should also be considered in assessing the benefits of IFN (Hepatology 1997;26: 422A). Patients with chronic hepatitis C may have diminished quality of life, independent of the degree of hepatic inflammation, or the mode of acquisition of the infection (Hepatology 1998;27:209–212). In our computation of quality-adjusted life years (QALY), 56% of the gain in QALYs with IFN treatment was attributed to the improvement in the quality of life of patients in the chronic hepatitis and compensated cirrhosis states, rather than prolongation of survival. Because patients often spend the most time in these two states, even a small improvement in their perceived quality of life becomes very significant when accumulated over a lifetime. As was clearly stated in our article, the objective of decision analytic models is not to create data where there are none. Instead, models such as ours put available data into perspective, based on actual estimates and realistic assumptions, so that they can be used to better inform clinical decision making. In this context, the strength of decision analysis lies in its ability to allow us to incorporate the results of sensitivity analyses taking into consideration a range of estimates of important variables. As Dr. Koretz proposes, what constitutes a reasonable range of estimates may be a matter of debate. In our opinion, however, withholding potentially beneficial treatment because of a lack of long-term outcome data may not be justified. W. RAY KIM JOHN J. POTERUCHA JOHN E. HERMANS TERRY M. THERNEAU E. ROLLAND DICKSON ROGER W. EVANS JOHN B. GROSS, Jr.