544 3. 4.
Correspondence Millonig G, et al. Hepatology 2008;48:1718–1723. Harata M, et al. Hepatol Res 2011;41:423–429.
Conflicts of interest The authors disclose no conflicts.
http://dx.doi.org/10.1053/j.gastro.2014.06.033
Gastroenterology Vol. 147, No. 2
References 1. 2. 3.
Panaccione R, et al. Gastroenterology 2014;146:392–400. Reich K, et al. Br J Dermatol 2013;168:1325–1334. Menter A, et al. J Am Acad Dermatol 2007;56:31. e1–31.e15.
Conflicts of interest The authors disclose no conflicts.
Are We Ready for Combination Ther- http://dx.doi.org/10.1053/j.gastro.2014.03.053 apy in Moderate-to-Severe Ulcerative Infliximab for Moderate to Severe Colitis? Ulcerative Colitis: The Jury Isn’t in Yet Dear Editor: The results of UC SUCCESS trial,1 which assessed the effect of combination therapy with infliximab (IFX) and azathioprine (AZA) in ulcerative colitis (UC), were recently published in Gastroenterology. Although this study provided insight into the effects of combination therapy, it raised various concerns, especially regarding the conclusions drawn from the results. We understand the reasons behind the low power and appreciate the decision to halt the trial owing to serious infusion reactions observed in another trial that evaluated the effects of IFX in patients with psoriasis (RESTORE2).2 We cannot comprehend that, despite using similar AZA dose, there were more adverse events in AZA arm than in IFXþAZA arm. Likewise, the lower incidence of infusion reactions observed in IFX and IFXþAZA arms does not align with previous reports,2,3 especially when such reactions from the RESTORE2 trial were cited as the reason to stop the UC SUCCESS trial prematurely. Based on these concerns, we are skeptical of our readiness for combination therapy in moderate-to-severe UC. Moreover, it may be misleading for the authors to suggest that combination therapy is superior to monotherapy with “either” agent, when the study did not actually demonstrate a clear superiority. Until we have a more robust study, the decision to pursue combination therapy should be individualized and weighed against the risk–benefit ratio as well as cost. YEONG YEH LEE Department of Medicine Section of Gastroenterology & Hepatology Georgia Regents University Augusta, Georgia and School of Medical Sciences Universiti Sains Malaysia Kubang Kerian Kelantan, Malaysia VENUGOPALAREDDY GANGIREDDY SANDEEP KHURANA SATISH S. C. RAO Department of Medicine Section of Gastroenterology & Hepatology Georgia Regents University Augusta, Georgia
Dear Editor: The study by Panaccione et al1 concluding that a combination of infliximab (IFX) and azathioprine (AZA) is superior to either drug as monotherapy in moderate to severe ulcerative colitis (UC) made for interesting reading, but also raised a number of questions. Despite an appropriate primary endpoint, defined as corticosteroid (CS)-free remission at 16 weeks, 3 aspects of the study design seem to have ensured that the true proportion of patients responding to AZA would be underestimated. First, patients not responding to AZA by week 8 were denoted as failure of therapy and given additional rescue IFX, even though the efficacy of AZA may not be fully evident for 17 weeks.2 Such a move ensured that a whopping 26 of 79 patients (32.9%) on AZA were prematurely classified as treatment failures. Second, CS needed to be tapered and stopped only by week 14, a clear 6 weeks after the time point for determining failure of AZA therapy. This meant that the remission achieved in some patients on IFX at 16 weeks, who were still on CS until 2 weeks earlier might have actually been owing to the latter drug, the AZA group not having such an advantage. Third, not estimating thiopurine methyltransferase activity before starting full-dose AZA as against current recommendations to do so3,4 contributed in part to a high number discontinuing therapy early in the AZA group owing to adverse events. This number 11 (13.7%), although not significantly different from the other groups, was nonetheless numerically higher and contributed to about 40% of the overall discontinuations in the AZA group. The latter event, we calculated using the chi square test, was significantly higher in the AZA group as against the other 2 groups (27 [33%] vs 14 [17%] and 17 [21%]; P ¼ .046], but the authors are silent about this, or its effect on the overall results of the study. Because of the limited duration under observation, the large numbers discontinuing therapy and variable periods of steroid-free remission complicated by a premature termination of the study, Kaplan–Meier estimates for the period of remission would have provided additional information, but the authors do not do so. The premature termination of the trial, that too because of an extraneous reason, is disappointing, because the consequent underpowering of the study weakened the authors’
August 2014
conclusions further. It would seem that some of the wide numerical differences between the 3 study groups at inclusion, such as the use of CS, the duration of disease, gender distribution, age of the patients, and fecal calprotectin levels, which did not attain significance, might have done so had the full complement of patients been enrolled. Surprisingly, the proportion of patients with a Mayo endoscopy subscore of 0 was not different between AZA and IFX (13.2% and 11.7%, respectively; P ¼ .783), despite the purported superiority of the latter drug in this trial, and the fact that week 16 may be too early for evaluating mucosal healing for slow-acting AZA compared with IFX.5 That the patients had to be IFX naïve at entry but not necessarily AZA naïve again likely introduced a bias by possibly allowing patients with prior nonresponse to the latter drug to be included. Consequently, all the study results, not just some of the secondary ones as the authors would have us believe, have to be interpreted with caution; the reported superiority of the combination therapy in the title of the article is clearly misleading. Disappointingly, the study excluded hospitalized patients with severe, extensive UC. The fact that IFX fares as well as cyclosporine6 in patients with severe UC (irrespective of the extent of the disease), who if anything need such therapy the most, should have prompted the authors to include all patients and not just those with limited severe colitis. It cannot be forgotten that up to three quarters of the patients with UC can be maintained in remission over 1 year with oral 5-aminosalicylic acid alone, a drug with a much more favorable adverse events profile.7,8 Where does this leave the 2 drugs AZA and IFX in the long-term management of UC? Do prematurely terminated trials like the one by the authors evaluating therapy over as short a period as 16 weeks suffice to change our therapeutic approach in a life-long disease like UC? Clearly, one cannot use the results of this study to inform current clinical practice. Further, better conducted, prospective studies are needed. NAGESH KAMATH Department of Gastroenterology and Hepatology Kasturba Medical College Manipal University Manipal, Karnataka, India ASHA KAMATH Department of Community Medicine Kasturba Medical College Manipal University Manipal, Karnataka, India C. GANESH PAI Department of Gastroenterology and Hepatology Kasturba Medical College Manipal University Manipal, Karnataka, India
References 1.
Panaccione R, et al. Gastroenterology 2014;146: 392–400.
Correspondence 2. 3. 4. 5. 6. 7. 8.
545
Boulton-Jones JR, et al. Aliment Pharmacol Ther 2000; 14:1561–1565. Mowat C, et al. Gut 2011;60:571–607. Lichtenstein GR, et al. Gastroenterology 2006;130: 935–939. Dassopoulos T, et al. Gastroenterol Clin N Am 2012; 41:393–409. Laharie D, et al. Lancet 2012;380:1909–1915. Kruis W, et al. Aliment Pharmacol Ther 2011;33:313–322. Feagan BG, et al. Cochrane Database Syst Rev 2012; 10:CD000544.
Conflicts of interest The authors disclose no conflicts.
http://dx.doi.org/10.1053/j.gastro.2014.02.060
Can Symptomatic Cancer Be Distinguished From Screen Detected Cancer? Dear Editor: The conclusion from the Utah Population Database that “interval” as opposed to “detected” colorectal cancers are more likely to be earlier stage with an improved prognosis1 is suspect; the authors cannot distinguish symptomatic from screen detected cancer. Symptomatic presentation is usually later stage with a worse prognosis. “Detected” cancers in the Utah study included, as the study authors acknowledge, an unknown proportion of symptomatic cases. In the interval cancer group, defined as diagnosis 6–60 months after an index colonoscopy, 57% of subjects had adenomas detected at the index colonoscopy, and thus many were likely undergoing asymptomatic surveillance colonoscopy at the time of cancer detection. Thus, “interval” cancers in this study may have been less likely to be symptomatic than “detected” cancers, which could explain the more favorable stage distribution and prognosis. In the PLCO flexible sigmoidoscopy screening trial, screen detected cancers were more likely earlier stage, with nearly 75% stage I or II, compared with a 51% rate for cancers not detected by screening.2 Additionally, in PLCO, screen detected cancers at baseline had a similar stage distribution as screen detected cancers at the subsequent screen, 3–5 years later.2 One should be cautious in drawing biologic conclusions about interval cancer from the Utah Population study. Further molecular study of interval cancer is advisable, but the circumstances surrounding presentation and diagnosis3 are needed to understand the biologic implications. ROBERT E. SCHOEN University of Pittsburgh Pittsburgh, Pennsylvania PAUL F. PINSKY National Cancer Institute Bethesda, Maryland
Correspondence Millonig G, et al. Hepatology 2008;48:1718–1723. Harata M, et al. Hepatol Res 2011;41:423–429.
Conflicts of interest The authors disclose no conflicts.
http://dx.doi.org/10.1053/j.gastro.2014.06.033
Gastroenterology Vol. 147, No. 2
References 1. 2. 3.
Panaccione R, et al. Gastroenterology 2014;146:392–400. Reich K, et al. Br J Dermatol 2013;168:1325–1334. Menter A, et al. J Am Acad Dermatol 2007;56:31. e1–31.e15.
Conflicts of interest The authors disclose no conflicts.
Are We Ready for Combination Ther- http://dx.doi.org/10.1053/j.gastro.2014.03.053 apy in Moderate-to-Severe Ulcerative Infliximab for Moderate to Severe Colitis? Ulcerative Colitis: The Jury Isn’t in Yet Dear Editor: The results of UC SUCCESS trial,1 which assessed the effect of combination therapy with infliximab (IFX) and azathioprine (AZA) in ulcerative colitis (UC), were recently published in Gastroenterology. Although this study provided insight into the effects of combination therapy, it raised various concerns, especially regarding the conclusions drawn from the results. We understand the reasons behind the low power and appreciate the decision to halt the trial owing to serious infusion reactions observed in another trial that evaluated the effects of IFX in patients with psoriasis (RESTORE2).2 We cannot comprehend that, despite using similar AZA dose, there were more adverse events in AZA arm than in IFXþAZA arm. Likewise, the lower incidence of infusion reactions observed in IFX and IFXþAZA arms does not align with previous reports,2,3 especially when such reactions from the RESTORE2 trial were cited as the reason to stop the UC SUCCESS trial prematurely. Based on these concerns, we are skeptical of our readiness for combination therapy in moderate-to-severe UC. Moreover, it may be misleading for the authors to suggest that combination therapy is superior to monotherapy with “either” agent, when the study did not actually demonstrate a clear superiority. Until we have a more robust study, the decision to pursue combination therapy should be individualized and weighed against the risk–benefit ratio as well as cost. YEONG YEH LEE Department of Medicine Section of Gastroenterology & Hepatology Georgia Regents University Augusta, Georgia and School of Medical Sciences Universiti Sains Malaysia Kubang Kerian Kelantan, Malaysia VENUGOPALAREDDY GANGIREDDY SANDEEP KHURANA SATISH S. C. RAO Department of Medicine Section of Gastroenterology & Hepatology Georgia Regents University Augusta, Georgia
Dear Editor: The study by Panaccione et al1 concluding that a combination of infliximab (IFX) and azathioprine (AZA) is superior to either drug as monotherapy in moderate to severe ulcerative colitis (UC) made for interesting reading, but also raised a number of questions. Despite an appropriate primary endpoint, defined as corticosteroid (CS)-free remission at 16 weeks, 3 aspects of the study design seem to have ensured that the true proportion of patients responding to AZA would be underestimated. First, patients not responding to AZA by week 8 were denoted as failure of therapy and given additional rescue IFX, even though the efficacy of AZA may not be fully evident for 17 weeks.2 Such a move ensured that a whopping 26 of 79 patients (32.9%) on AZA were prematurely classified as treatment failures. Second, CS needed to be tapered and stopped only by week 14, a clear 6 weeks after the time point for determining failure of AZA therapy. This meant that the remission achieved in some patients on IFX at 16 weeks, who were still on CS until 2 weeks earlier might have actually been owing to the latter drug, the AZA group not having such an advantage. Third, not estimating thiopurine methyltransferase activity before starting full-dose AZA as against current recommendations to do so3,4 contributed in part to a high number discontinuing therapy early in the AZA group owing to adverse events. This number 11 (13.7%), although not significantly different from the other groups, was nonetheless numerically higher and contributed to about 40% of the overall discontinuations in the AZA group. The latter event, we calculated using the chi square test, was significantly higher in the AZA group as against the other 2 groups (27 [33%] vs 14 [17%] and 17 [21%]; P ¼ .046], but the authors are silent about this, or its effect on the overall results of the study. Because of the limited duration under observation, the large numbers discontinuing therapy and variable periods of steroid-free remission complicated by a premature termination of the study, Kaplan–Meier estimates for the period of remission would have provided additional information, but the authors do not do so. The premature termination of the trial, that too because of an extraneous reason, is disappointing, because the consequent underpowering of the study weakened the authors’
August 2014
conclusions further. It would seem that some of the wide numerical differences between the 3 study groups at inclusion, such as the use of CS, the duration of disease, gender distribution, age of the patients, and fecal calprotectin levels, which did not attain significance, might have done so had the full complement of patients been enrolled. Surprisingly, the proportion of patients with a Mayo endoscopy subscore of 0 was not different between AZA and IFX (13.2% and 11.7%, respectively; P ¼ .783), despite the purported superiority of the latter drug in this trial, and the fact that week 16 may be too early for evaluating mucosal healing for slow-acting AZA compared with IFX.5 That the patients had to be IFX naïve at entry but not necessarily AZA naïve again likely introduced a bias by possibly allowing patients with prior nonresponse to the latter drug to be included. Consequently, all the study results, not just some of the secondary ones as the authors would have us believe, have to be interpreted with caution; the reported superiority of the combination therapy in the title of the article is clearly misleading. Disappointingly, the study excluded hospitalized patients with severe, extensive UC. The fact that IFX fares as well as cyclosporine6 in patients with severe UC (irrespective of the extent of the disease), who if anything need such therapy the most, should have prompted the authors to include all patients and not just those with limited severe colitis. It cannot be forgotten that up to three quarters of the patients with UC can be maintained in remission over 1 year with oral 5-aminosalicylic acid alone, a drug with a much more favorable adverse events profile.7,8 Where does this leave the 2 drugs AZA and IFX in the long-term management of UC? Do prematurely terminated trials like the one by the authors evaluating therapy over as short a period as 16 weeks suffice to change our therapeutic approach in a life-long disease like UC? Clearly, one cannot use the results of this study to inform current clinical practice. Further, better conducted, prospective studies are needed. NAGESH KAMATH Department of Gastroenterology and Hepatology Kasturba Medical College Manipal University Manipal, Karnataka, India ASHA KAMATH Department of Community Medicine Kasturba Medical College Manipal University Manipal, Karnataka, India C. GANESH PAI Department of Gastroenterology and Hepatology Kasturba Medical College Manipal University Manipal, Karnataka, India
References 1.
Panaccione R, et al. Gastroenterology 2014;146: 392–400.
Correspondence 2. 3. 4. 5. 6. 7. 8.
545
Boulton-Jones JR, et al. Aliment Pharmacol Ther 2000; 14:1561–1565. Mowat C, et al. Gut 2011;60:571–607. Lichtenstein GR, et al. Gastroenterology 2006;130: 935–939. Dassopoulos T, et al. Gastroenterol Clin N Am 2012; 41:393–409. Laharie D, et al. Lancet 2012;380:1909–1915. Kruis W, et al. Aliment Pharmacol Ther 2011;33:313–322. Feagan BG, et al. Cochrane Database Syst Rev 2012; 10:CD000544.
Conflicts of interest The authors disclose no conflicts.
http://dx.doi.org/10.1053/j.gastro.2014.02.060
Can Symptomatic Cancer Be Distinguished From Screen Detected Cancer? Dear Editor: The conclusion from the Utah Population Database that “interval” as opposed to “detected” colorectal cancers are more likely to be earlier stage with an improved prognosis1 is suspect; the authors cannot distinguish symptomatic from screen detected cancer. Symptomatic presentation is usually later stage with a worse prognosis. “Detected” cancers in the Utah study included, as the study authors acknowledge, an unknown proportion of symptomatic cases. In the interval cancer group, defined as diagnosis 6–60 months after an index colonoscopy, 57% of subjects had adenomas detected at the index colonoscopy, and thus many were likely undergoing asymptomatic surveillance colonoscopy at the time of cancer detection. Thus, “interval” cancers in this study may have been less likely to be symptomatic than “detected” cancers, which could explain the more favorable stage distribution and prognosis. In the PLCO flexible sigmoidoscopy screening trial, screen detected cancers were more likely earlier stage, with nearly 75% stage I or II, compared with a 51% rate for cancers not detected by screening.2 Additionally, in PLCO, screen detected cancers at baseline had a similar stage distribution as screen detected cancers at the subsequent screen, 3–5 years later.2 One should be cautious in drawing biologic conclusions about interval cancer from the Utah Population study. Further molecular study of interval cancer is advisable, but the circumstances surrounding presentation and diagnosis3 are needed to understand the biologic implications. ROBERT E. SCHOEN University of Pittsburgh Pittsburgh, Pennsylvania PAUL F. PINSKY National Cancer Institute Bethesda, Maryland
