- Email: [email protected]
NSAID trials, sporadic adenomas, and conservative inferences
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
February 1996
CORRESPONDENCE 655
PHILIP LAVORI ROBERT EDSON
Cooperative Studies Program Coordinating Center VA Palo Alto Health Care System 3801 Miranda Avenue Palo Alto, California 94304 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. DuBois RN. Nonsteroidal anti-inflammatory drug use and sporadic colorectal adenomas. Gastroenterology 1995;108:1310–1314. 3. Giardello FM, Hamilton SR, Krush AJ, Piantadosi S, Hylind LM, Celano P, Booker SV, Robinson CR, Offerhaus GJA. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med 1993;328:1313–1316. 4. Tonelli F, Valanzano R, Dolara P. Sulindac therapy of colorectal polyps in familial adenomatous polyposis. Dig Dis 1994;12:259– 264.
Chemosensitivity in Irritable Bowel Syndrome Dear Sir: The report by Lembo et al.1 and the accompanying editorial2 have called attention to the ‘‘hypersensitivity’’ of the gut mucosa, including its yet to be studied chemosensitivity in irritable bowel syndrome. Reviewing our previous study of prevalence of irritable bowel syndrome in a non-Western population,3 we found data regarding people’s reaction to spicy food which might be relevant in this regard. This part of data was published in our local journal.4 Among a population of 1077, 54.6% of people who had symptoms satisfying
the criteria of ‘‘spastic irritable colon’’5 reported abdominal pain after eating spicy food, in contrast to 24.4% of people who did not have that symptom complex (P õ 0.05). This finding is consistent with our impression from the clinical observation that patients with irritable bowel syndrome in our ‘‘spice loving society’’ are intolerant to the local delicacy. If future investigations confirm that patients with irritable bowel syndrome is indeed hypersensitive to capsaicin, we might have a simple clinical test using capsaicin, or the natural product capsicum, in conjunction with simple objective parameters such as intestinal transit times.6 AMNACH SRIRATANABAN, M.D.
Division of Gastroenterology Department of Medicine Faculty of Medicine Chulalongkorn University Bangkok 10400, Thailand 1. Lembo T, Munakata J, Mertz H, Niazi N, Kodner A, Nikas V, Mayer EA. Evidence for the hypersensitivity of lumbar splanchnic afferents in irritable bowel syndrome. Gastroenterology 1994; 107:1686–1696. 2. Andrews PL. Irritable bowel syndrome: just a pain in the butt? Gastroenterology 1994;107:1886–1890. 3. Danivat D, Tankeyoon M, Sriratanaban A. Prevalance of irritable bowel syndrome in a non-Western population. Br Med J 1988;296:1710. 4. Danvivat D, Tankeyoon M, Sriratanaban A. A study of bowel patterns in Thai population. Chula Med J 1988;32:803–809. 5. Thomson WG, Heaton KW. Functional bowel disorders in apparently healthy people. Gastroenterology 1980;79:283–288. 6. Hinton JM, Lennard-Jones SE, Young AC. A new method of studying gut transit times using radiopaque markers. Gut 1969;10:842– 847.
Correction Miller LS, Liu J-B, Colizzo FP, et al. Correlation of high-frequency esophageal ultrasonography and manometry in the study of esophageal motility. Gastroenterology 1995;109:832–837.
The correct spelling of the seventh author of this paper is Kyle Helwig.
/ m4787$0057
01-17-96 14:21:34
gasas
WBS-Gastro
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
February 1996
CORRESPONDENCE 655
PHILIP LAVORI ROBERT EDSON
Cooperative Studies Program Coordinating Center VA Palo Alto Health Care System 3801 Miranda Avenue Palo Alto, California 94304 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. DuBois RN. Nonsteroidal anti-inflammatory drug use and sporadic colorectal adenomas. Gastroenterology 1995;108:1310–1314. 3. Giardello FM, Hamilton SR, Krush AJ, Piantadosi S, Hylind LM, Celano P, Booker SV, Robinson CR, Offerhaus GJA. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med 1993;328:1313–1316. 4. Tonelli F, Valanzano R, Dolara P. Sulindac therapy of colorectal polyps in familial adenomatous polyposis. Dig Dis 1994;12:259– 264.
Chemosensitivity in Irritable Bowel Syndrome Dear Sir: The report by Lembo et al.1 and the accompanying editorial2 have called attention to the ‘‘hypersensitivity’’ of the gut mucosa, including its yet to be studied chemosensitivity in irritable bowel syndrome. Reviewing our previous study of prevalence of irritable bowel syndrome in a non-Western population,3 we found data regarding people’s reaction to spicy food which might be relevant in this regard. This part of data was published in our local journal.4 Among a population of 1077, 54.6% of people who had symptoms satisfying
the criteria of ‘‘spastic irritable colon’’5 reported abdominal pain after eating spicy food, in contrast to 24.4% of people who did not have that symptom complex (P õ 0.05). This finding is consistent with our impression from the clinical observation that patients with irritable bowel syndrome in our ‘‘spice loving society’’ are intolerant to the local delicacy. If future investigations confirm that patients with irritable bowel syndrome is indeed hypersensitive to capsaicin, we might have a simple clinical test using capsaicin, or the natural product capsicum, in conjunction with simple objective parameters such as intestinal transit times.6 AMNACH SRIRATANABAN, M.D.
Division of Gastroenterology Department of Medicine Faculty of Medicine Chulalongkorn University Bangkok 10400, Thailand 1. Lembo T, Munakata J, Mertz H, Niazi N, Kodner A, Nikas V, Mayer EA. Evidence for the hypersensitivity of lumbar splanchnic afferents in irritable bowel syndrome. Gastroenterology 1994; 107:1686–1696. 2. Andrews PL. Irritable bowel syndrome: just a pain in the butt? Gastroenterology 1994;107:1886–1890. 3. Danivat D, Tankeyoon M, Sriratanaban A. Prevalance of irritable bowel syndrome in a non-Western population. Br Med J 1988;296:1710. 4. Danvivat D, Tankeyoon M, Sriratanaban A. A study of bowel patterns in Thai population. Chula Med J 1988;32:803–809. 5. Thomson WG, Heaton KW. Functional bowel disorders in apparently healthy people. Gastroenterology 1980;79:283–288. 6. Hinton JM, Lennard-Jones SE, Young AC. A new method of studying gut transit times using radiopaque markers. Gut 1969;10:842– 847.
Correction Miller LS, Liu J-B, Colizzo FP, et al. Correlation of high-frequency esophageal ultrasonography and manometry in the study of esophageal motility. Gastroenterology 1995;109:832–837.
The correct spelling of the seventh author of this paper is Kyle Helwig.
/ m4787$0057
01-17-96 14:21:34
gasas
WBS-Gastro