- Email: [email protected]
Screening for hemochromatosis: Additional considerations
February 1996
CORRESPONDENCE 653
only one serious complication, pancreatitis, found in patients taking mesalamine. While there is mounting evidence that 6-MP may be used safely on a long term basis, it is associated with both early and long-term toxicity. In the study by O’Donohue et al. cited by Dr. Korelitz, there was one death attributable to 6-MP.3 We believe that the value of our study is that it is one of the first to show that mesalamine is effective in preventing postoperative recurrences. However, as stated in our report, further clinical trials are required in this group of patients to evaluate other therapeutic agents. We agree with Dr. Korelitz that immunosuppressants might have a role as prophylactic agents, particularly in patients at high risk of recurrence or those with residual disease. However, conclusive evidence on the effectiveness of immunosuppressants in this cohort of patients is not available at the present time. ROBIN S. MCLEOD, M.D.
University of Toronto and Members of the PostOperative Crohn’s Disease Trial Toronto, Ontario, Canada 1. Korelitz BI. Drug choice in preventing postoperative Crohn’s disease. Gastroenterology 1996;110:652. 2. McLeod RS, Wolff BG, Steinhart AH, Carryer PW, O’Rourke K, Andrews DF, Blair JE, Cangemi JR, Cohen Z, Cullen JB, Chaytor RG, Greenberg GR, Jaffer NY, Jeejeebhoy KN, MacCarty RL. Reddy RL, Weiland LH. Prophylactic mesalamine treatment decreases postoperative recurrence of Crohn’s disease. Gastroenterology 1995;109:404–413. 3. O’Donoghue DP, Dawson AM, Powell-Tuck J, Brown RL, LennardJones JE. Double-blinded withdrawal of azathioprine as maintenance treatment of Crohn’s disease. Lancet 1978;2:955–957.
Screening for Hemochromatosis: Additional Considerations Dear Sir: We commend Adams et al.1 for their decision analysis model; their conclusions are similar to that of our analysis2 and serve to reemphasize the need to increase the awareness of hereditary hemochromatosis (HH) among practitioners and to make a case for routine screening for this disorder. Two issues that relate to their analysis are worthy of comment. First, the use of their database to derive the probability of developing life-threatening disease complications may be flawed. The cohort of patients accumulated by Adams et al. during a period of 30 years undoubtedly represents a select group of patients with HH, many referred for symptomatic disease. The application of a general screening strategy is likely to identify less advanced cases and, arguably, a smaller proportion of these may ever develop life-threatening complications. This would be particularly true in the case of blood donors who tend to be young, healthy individuals and have normal liver enzyme levels. Studies of asymptomatic siblings suggest that a significant proportion do have clinically relevant iron overload,3 but the true proportion of all homozygous individuals who will develop significant tissue iron accumulation remains somewhat uncertain. Our own sensitivity analysis2 revealed that this proportion has considerable influence on the value of screening. Second, any analysis of routine screening iron studies must account for the evaluation and management of incidentally detected iron deficiency. Our own data derived from screening more than 4000 primary care patients with serum transferrin saturation levels reveals that 8% of the women younger than 50 years old, 3% of the women older
/ m4787$0057
01-17-96 14:21:34
gasas
than 50 years old, and 1% of men have a transferrin saturation level of õ15% and serum ferritin level of õ20 ng/mL, indicative of iron deficiency (unpublished observations). Although many of these individuals are young women with menstrual blood loss as an etiology for their iron deficiency, a significant proportion would require further workup to determine the cause of iron deficiency. The added cost and benefit of this workup needs to be considered in determining the cost-effectiveness of iron screening. Regardless of these issues, both the analysis of Adams et al. and our own should underscore the need to increase awareness of HH among practitioners and to provoke discussion regarding routine screening. Large screening studies are urgently needed to validate both models and establish the rationale for routine screening. PRADYUMNA D. PHATAK, M.D. RONALD L. SHAM, M.D. JOSEPH D. CAPPUCCIO, M.D.
Hematology and General Medicine Units Rochester General Hospital 1425 Portland Avenue Rochester, New York 14621 1. Adams PC, Gregor JC, Kertesz AE, Valberg LS. Screening blood donors for hereditary hemochromatosis: decision analysis model based on a 30-year database. Gastroenterology 1995;109:177– 188. 2. Phatak PD, Guzman G, Woll JE, Robeson A, Phelps CE. Cost-effectiveness of screening for hereditary hemochromatosis. Arch Intern Med 1994;154:769–776. 3. Powell LW, Summers KM, Board PG, Axelsen E, Webb S, Halliday JW. Expression of hemochromatosis in homozygous subjects: implications for early diagnosis and prevention. Gastroenterology 1990;98:1625–1632.
Reply. We were gratified that the results of our model were very similar to the theoretical model produced by Phatak et al.1 We do not consider our estimates based on 30 years of clinical experience with hemochromatosis to be flawed but rather to be the best available estimate from our population area. We believe that these estimates are preferable to hypothetical data and reports from other countries. We would welcome further data becoming available from population screening studies elsewhere. The true penetrance of the disease will require a genetic test. We did not consider the potential cost of investigating iron deficiency anemia identified in a screened population because anemic patients are not eligible as blood donors. However, a screening strategy in a primary care setting should consider the cost of the investigation of iron deficiency. This approach has been accommodated in a recent report by Baer et al.2 In an accompanying editorial, Kushner concluded that we had established the value of the unsaturated iron-binding capacity test in screening hemochromatosis.3 Although the test has shown a strong correlation with transferrin saturation at a reduced cost at our center, the actual value of the test has yet to be established in a large screened population. We would agree that further screening studies to validate the many assumptions in these models is ideal but will be dependent on financial funding that has not been forthcoming in many countries in which population screening has been advocated, including Canada. PAUL C. ADAMS, M.D. LESLIE S. VALBERG, M.D.
University Hospital London, Ontario, Canada
WBS-Gastro
654 CORRESPONDENCE
GASTROENTEROLOGY Vol. 110, No. 2
1. Phatak PD, Guzman G, Woll JE, Robeson A, Phelps CE. Cost-effectiveness of screening for hereditary hemochromatosis. Arch Intern Med 1994;154:769–776. 2. Baer DM, Simons JL, Staples RL, Rumore GJ, Morton DJ. Hemochromatosis screening in asymptomatic ambulatory men 30 years of age and older. Am J Med 1995;98:464–468. 3. Kushner JP. Screening for hemochromatosis. Gastroenterology 1995;109:315–316.
ERNEST HAWK, M.D., M.P.H. SHEILA PRINDIVILLE, M.D., M.P.H. GARY KELLOFF, M.D.
NSAID Trials, Sporadic Adenomas, and Conservative Inferences Dear Sir: Conduct of clinical chemoprevention trials is difficult for several reasons, including their required size, duration, and cost. Although several groups are attempting to address these issues by innovative means, there remains great interest in trials that characterize chemopreventive efficacy using end points that are directly relevant to clinical practice. Ladenheim et al.1 should be congratulated on the completion of the first randomized clinical trial evaluating the efficacy of sulindac in a sporadic polyp cohort, yet there are several elements of the trial’s design that should be considered before accepting its ‘‘negative’’ results. The trial included subjects who had used aspirin (of unknown duration) up to the time of randomization and failed to stratify their allocation on entry. This is potentially problematic because subjects harboring polyps, particularly adenomas, while using aspirin might be anticipated to be relatively resistant to any other nonsteroidal anti-inflammatory drugs (NSAIDs) chemopreventive effect compared with those not previously exposed to aspirin. Because the distribution of these individuals was disproportionate among the two groups (36% in the sulindac arm and 18% in the placebo arm), an unintentional selection bias toward nonresponse in the sulindac arm may have occurred. We wonder if an additional efficacy analysis addressing the effect of this intervention in adenoma subjects not previously exposed to aspirin who completed the 4-month trial would provide the best test of sulindac’s efficacy on cancer risk available in this trial. Clearly, such an analysis may be complicated by the small numbers of individuals meeting these criteria; indeed, it is possible that this trial’s actual power, when considering the truly relevant subset at elevated cancer risk, may be lower than the estimates presented. Additional considerations that may have contributed to the finding of a statistically ‘‘null effect’’ in this trial include its limited evaluation of potential confounders such as dietary fat and fiber (though randomization would have tended to control for any differential appropriation), its limited accrual compared with screened individuals (offering a potential for other unintentional selection biases because the trial accrued 27% of screened individuals), its small size, and its limited period of intervention (FAP trials have evaluated efficacy of sulindac during a 4–9-month period, but in these cases, each patient would be anticipated to harbor many adenomatous polyps, potentially increasing the power of the studies and providing greater assurance of the subjects’ cancer risk status). We believe the potential and realized limitations of this trial argue against all but the most conservative interpretations of its results, whether positive or negative. Additionally, considering that the published literature relating to the evaluation of effects of NSAIDs on sporadic polyps in clinical trials includes only 31 patients treated during a period of 4– 6 months,1,2 we believe that further trials evaluating all potential aspects of effects of NSAIDs, including adenoma regression, are warranted and welcome.3 Certainly, the cumulative animal, epidemiolog-
/ m4787$0057
01-17-96 14:21:34
ical, and human trial data available thus far offers strong support for further investigation into the use of NSAIDs in cancer prevention; ideally, these trials will emphasize mechanistic inquiries and consider approaches that might improve the therapeutic index of NSAIDs used for these indications. This pilot trial by Ladenheim et al. reminds us of the difficulties inherent in the conduct of these trials and the need to carefully consider a number of additional design elements in the next generation of studies.
gasas
Division of Cancer Prevention & Control National Cancer Institute Bethesda, Maryland 20892 1. Ladenheim J, Garcia G, Titzer D, Herzenberg H, Lavori P, Edson R, Omary MB. Effect of sulindac on sporadic colonic polyps. Gastroenterology 1995;108:1083–1087. 2. Hixson LJ, Earnest DL, Fennerty MB, et al. NSAID effect on sporadic colon polyps. Am J Gastroenterology 1993;88:1652–1656. 3. DuBois RN. Nonsteroidal anti-inflammatory drug use and sporadic colorectal adenomas. Gastroenterology 1995;108:1310–1314.
Reply. We thank Hawk et al. for their comments and interest in our study addressing the effect of sulindac on sporadic colonic polyps. As we stated,1 although our study was negative in terms of a significant clinical effect of sulindac on colonic polyps, it is possible that a statistically significant effect could have been obtained if a much larger number of patients were to be enrolled. However, on analysis of our data, we believed that a ‘‘clinically useful’’ effect was unlikely to justify extending our study based on the low therapeutic index and the risk of NSAID-induced complications. We agree with others2 that studies addressing the use of NSAIDs as prevention agents (particularly in lower doses) against colonic adenomas are warranted, but studies addressing their use as a treatment modality would be difficult to justify given their apparent low benefits. With regard to NSAID intake in patients enrolled in our study, we agree with Hawk et al. that the 12 patients (8 in the sulindac group and 4 in the placebo group) who were taking 80–325 mg aspirin on a routine basis before enrollment in the study could be more resistant to an NSAID-induced polyp progression effect. Four of the 8 patients in the sulindac group and 2 of the 4 patients in the placebo group had residual unchanged adenomas, and 1 patient from each group had regressed polyps, suggesting that the effect was proportionate for both groups. The potential for resistance to continued sulindac treatment (i.e., regimen extending up to 9 months) has been suggested, and it is unclear how much compliance plays in such resistance.3,4 JAY LADENHEIM GABRIEL GARCIA DIANE TITZER M. BISHR OMARY
Department of Medicine VA Palo Alto Health Care System Stanford University School of Medicine 3801 Miranda Avenue Palo Alto, California 94304 HOWARD HERZENBERG
Santa Clara Kaiser Hospital Santa Clara, California
WBS-Gastro
CORRESPONDENCE 653
only one serious complication, pancreatitis, found in patients taking mesalamine. While there is mounting evidence that 6-MP may be used safely on a long term basis, it is associated with both early and long-term toxicity. In the study by O’Donohue et al. cited by Dr. Korelitz, there was one death attributable to 6-MP.3 We believe that the value of our study is that it is one of the first to show that mesalamine is effective in preventing postoperative recurrences. However, as stated in our report, further clinical trials are required in this group of patients to evaluate other therapeutic agents. We agree with Dr. Korelitz that immunosuppressants might have a role as prophylactic agents, particularly in patients at high risk of recurrence or those with residual disease. However, conclusive evidence on the effectiveness of immunosuppressants in this cohort of patients is not available at the present time. ROBIN S. MCLEOD, M.D.
University of Toronto and Members of the PostOperative Crohn’s Disease Trial Toronto, Ontario, Canada 1. Korelitz BI. Drug choice in preventing postoperative Crohn’s disease. Gastroenterology 1996;110:652. 2. McLeod RS, Wolff BG, Steinhart AH, Carryer PW, O’Rourke K, Andrews DF, Blair JE, Cangemi JR, Cohen Z, Cullen JB, Chaytor RG, Greenberg GR, Jaffer NY, Jeejeebhoy KN, MacCarty RL. Reddy RL, Weiland LH. Prophylactic mesalamine treatment decreases postoperative recurrence of Crohn’s disease. Gastroenterology 1995;109:404–413. 3. O’Donoghue DP, Dawson AM, Powell-Tuck J, Brown RL, LennardJones JE. Double-blinded withdrawal of azathioprine as maintenance treatment of Crohn’s disease. Lancet 1978;2:955–957.
Screening for Hemochromatosis: Additional Considerations Dear Sir: We commend Adams et al.1 for their decision analysis model; their conclusions are similar to that of our analysis2 and serve to reemphasize the need to increase the awareness of hereditary hemochromatosis (HH) among practitioners and to make a case for routine screening for this disorder. Two issues that relate to their analysis are worthy of comment. First, the use of their database to derive the probability of developing life-threatening disease complications may be flawed. The cohort of patients accumulated by Adams et al. during a period of 30 years undoubtedly represents a select group of patients with HH, many referred for symptomatic disease. The application of a general screening strategy is likely to identify less advanced cases and, arguably, a smaller proportion of these may ever develop life-threatening complications. This would be particularly true in the case of blood donors who tend to be young, healthy individuals and have normal liver enzyme levels. Studies of asymptomatic siblings suggest that a significant proportion do have clinically relevant iron overload,3 but the true proportion of all homozygous individuals who will develop significant tissue iron accumulation remains somewhat uncertain. Our own sensitivity analysis2 revealed that this proportion has considerable influence on the value of screening. Second, any analysis of routine screening iron studies must account for the evaluation and management of incidentally detected iron deficiency. Our own data derived from screening more than 4000 primary care patients with serum transferrin saturation levels reveals that 8% of the women younger than 50 years old, 3% of the women older
/ m4787$0057
01-17-96 14:21:34
gasas
than 50 years old, and 1% of men have a transferrin saturation level of õ15% and serum ferritin level of õ20 ng/mL, indicative of iron deficiency (unpublished observations). Although many of these individuals are young women with menstrual blood loss as an etiology for their iron deficiency, a significant proportion would require further workup to determine the cause of iron deficiency. The added cost and benefit of this workup needs to be considered in determining the cost-effectiveness of iron screening. Regardless of these issues, both the analysis of Adams et al. and our own should underscore the need to increase awareness of HH among practitioners and to provoke discussion regarding routine screening. Large screening studies are urgently needed to validate both models and establish the rationale for routine screening. PRADYUMNA D. PHATAK, M.D. RONALD L. SHAM, M.D. JOSEPH D. CAPPUCCIO, M.D.
Hematology and General Medicine Units Rochester General Hospital 1425 Portland Avenue Rochester, New York 14621 1. Adams PC, Gregor JC, Kertesz AE, Valberg LS. Screening blood donors for hereditary hemochromatosis: decision analysis model based on a 30-year database. Gastroenterology 1995;109:177– 188. 2. Phatak PD, Guzman G, Woll JE, Robeson A, Phelps CE. Cost-effectiveness of screening for hereditary hemochromatosis. Arch Intern Med 1994;154:769–776. 3. Powell LW, Summers KM, Board PG, Axelsen E, Webb S, Halliday JW. Expression of hemochromatosis in homozygous subjects: implications for early diagnosis and prevention. Gastroenterology 1990;98:1625–1632.
Reply. We were gratified that the results of our model were very similar to the theoretical model produced by Phatak et al.1 We do not consider our estimates based on 30 years of clinical experience with hemochromatosis to be flawed but rather to be the best available estimate from our population area. We believe that these estimates are preferable to hypothetical data and reports from other countries. We would welcome further data becoming available from population screening studies elsewhere. The true penetrance of the disease will require a genetic test. We did not consider the potential cost of investigating iron deficiency anemia identified in a screened population because anemic patients are not eligible as blood donors. However, a screening strategy in a primary care setting should consider the cost of the investigation of iron deficiency. This approach has been accommodated in a recent report by Baer et al.2 In an accompanying editorial, Kushner concluded that we had established the value of the unsaturated iron-binding capacity test in screening hemochromatosis.3 Although the test has shown a strong correlation with transferrin saturation at a reduced cost at our center, the actual value of the test has yet to be established in a large screened population. We would agree that further screening studies to validate the many assumptions in these models is ideal but will be dependent on financial funding that has not been forthcoming in many countries in which population screening has been advocated, including Canada. PAUL C. ADAMS, M.D. LESLIE S. VALBERG, M.D.
University Hospital London, Ontario, Canada
WBS-Gastro
654 CORRESPONDENCE
GASTROENTEROLOGY Vol. 110, No. 2
1. Phatak PD, Guzman G, Woll JE, Robeson A, Phelps CE. Cost-effectiveness of screening for hereditary hemochromatosis. Arch Intern Med 1994;154:769–776. 2. Baer DM, Simons JL, Staples RL, Rumore GJ, Morton DJ. Hemochromatosis screening in asymptomatic ambulatory men 30 years of age and older. Am J Med 1995;98:464–468. 3. Kushner JP. Screening for hemochromatosis. Gastroenterology 1995;109:315–316.
ERNEST HAWK, M.D., M.P.H. SHEILA PRINDIVILLE, M.D., M.P.H. GARY KELLOFF, M.D.
NSAID Trials, Sporadic Adenomas, and Conservative Inferences Dear Sir: Conduct of clinical chemoprevention trials is difficult for several reasons, including their required size, duration, and cost. Although several groups are attempting to address these issues by innovative means, there remains great interest in trials that characterize chemopreventive efficacy using end points that are directly relevant to clinical practice. Ladenheim et al.1 should be congratulated on the completion of the first randomized clinical trial evaluating the efficacy of sulindac in a sporadic polyp cohort, yet there are several elements of the trial’s design that should be considered before accepting its ‘‘negative’’ results. The trial included subjects who had used aspirin (of unknown duration) up to the time of randomization and failed to stratify their allocation on entry. This is potentially problematic because subjects harboring polyps, particularly adenomas, while using aspirin might be anticipated to be relatively resistant to any other nonsteroidal anti-inflammatory drugs (NSAIDs) chemopreventive effect compared with those not previously exposed to aspirin. Because the distribution of these individuals was disproportionate among the two groups (36% in the sulindac arm and 18% in the placebo arm), an unintentional selection bias toward nonresponse in the sulindac arm may have occurred. We wonder if an additional efficacy analysis addressing the effect of this intervention in adenoma subjects not previously exposed to aspirin who completed the 4-month trial would provide the best test of sulindac’s efficacy on cancer risk available in this trial. Clearly, such an analysis may be complicated by the small numbers of individuals meeting these criteria; indeed, it is possible that this trial’s actual power, when considering the truly relevant subset at elevated cancer risk, may be lower than the estimates presented. Additional considerations that may have contributed to the finding of a statistically ‘‘null effect’’ in this trial include its limited evaluation of potential confounders such as dietary fat and fiber (though randomization would have tended to control for any differential appropriation), its limited accrual compared with screened individuals (offering a potential for other unintentional selection biases because the trial accrued 27% of screened individuals), its small size, and its limited period of intervention (FAP trials have evaluated efficacy of sulindac during a 4–9-month period, but in these cases, each patient would be anticipated to harbor many adenomatous polyps, potentially increasing the power of the studies and providing greater assurance of the subjects’ cancer risk status). We believe the potential and realized limitations of this trial argue against all but the most conservative interpretations of its results, whether positive or negative. Additionally, considering that the published literature relating to the evaluation of effects of NSAIDs on sporadic polyps in clinical trials includes only 31 patients treated during a period of 4– 6 months,1,2 we believe that further trials evaluating all potential aspects of effects of NSAIDs, including adenoma regression, are warranted and welcome.3 Certainly, the cumulative animal, epidemiolog-
/ m4787$0057
01-17-96 14:21:34
ical, and human trial data available thus far offers strong support for further investigation into the use of NSAIDs in cancer prevention; ideally, these trials will emphasize mechanistic inquiries and consider approaches that might improve the therapeutic index of NSAIDs used for these indications. This pilot trial by Ladenheim et al. reminds us of the difficulties inherent in the conduct of these trials and the need to carefully consider a number of additional design elements in the next generation of studies.
gasas
Division of Cancer Prevention & Control National Cancer Institute Bethesda, Maryland 20892 1. Ladenheim J, Garcia G, Titzer D, Herzenberg H, Lavori P, Edson R, Omary MB. Effect of sulindac on sporadic colonic polyps. Gastroenterology 1995;108:1083–1087. 2. Hixson LJ, Earnest DL, Fennerty MB, et al. NSAID effect on sporadic colon polyps. Am J Gastroenterology 1993;88:1652–1656. 3. DuBois RN. Nonsteroidal anti-inflammatory drug use and sporadic colorectal adenomas. Gastroenterology 1995;108:1310–1314.
Reply. We thank Hawk et al. for their comments and interest in our study addressing the effect of sulindac on sporadic colonic polyps. As we stated,1 although our study was negative in terms of a significant clinical effect of sulindac on colonic polyps, it is possible that a statistically significant effect could have been obtained if a much larger number of patients were to be enrolled. However, on analysis of our data, we believed that a ‘‘clinically useful’’ effect was unlikely to justify extending our study based on the low therapeutic index and the risk of NSAID-induced complications. We agree with others2 that studies addressing the use of NSAIDs as prevention agents (particularly in lower doses) against colonic adenomas are warranted, but studies addressing their use as a treatment modality would be difficult to justify given their apparent low benefits. With regard to NSAID intake in patients enrolled in our study, we agree with Hawk et al. that the 12 patients (8 in the sulindac group and 4 in the placebo group) who were taking 80–325 mg aspirin on a routine basis before enrollment in the study could be more resistant to an NSAID-induced polyp progression effect. Four of the 8 patients in the sulindac group and 2 of the 4 patients in the placebo group had residual unchanged adenomas, and 1 patient from each group had regressed polyps, suggesting that the effect was proportionate for both groups. The potential for resistance to continued sulindac treatment (i.e., regimen extending up to 9 months) has been suggested, and it is unclear how much compliance plays in such resistance.3,4 JAY LADENHEIM GABRIEL GARCIA DIANE TITZER M. BISHR OMARY
Department of Medicine VA Palo Alto Health Care System Stanford University School of Medicine 3801 Miranda Avenue Palo Alto, California 94304 HOWARD HERZENBERG
Santa Clara Kaiser Hospital Santa Clara, California
WBS-Gastro