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Psychotherapy and functional dyspepsia: brain-gut interactions
278
What’s New in GI
than endoanal MRI. Anal EUS and endoanal MRI have equivalent results in the evaluation of external anal sphincter injury. A. Matamoros, Jr., M.D.
Chemoprevention Adds Up Torrance CJ, Jackson PE, Montgomery E, et al. Combinatorial chemoprevention of intestinal neoplasia. Nat Med 2000;6:1024 – 8. Although a variety of agents protect against colorectal carcinogenesis, their modest efficacy and potential toxicity have limited clinical utility. For example, the cyclo-oxygenase 2–selective nonsteroidal anti-inflammatory drug celecoxib has recently received Food and Drug Administration approval for polyp suppression in familial adenomatous polyposis, although it decreased adenoma number by only one third. Other chemopreventive agents such as ursodeoxycholic acid, calcium, fiber, folate, and estrogens offer a similar 30% to 60%risk reduction. Newer agents are being developed to target specific signaling pathways that are dysregulated during neoplastic transformation. Torrance et al. assess the novel agent EKB-569 alone and in combination with the nonsteroidal anti-inflammatory drug sulindac by utilizing the mouse model of familial adenomatous polyposis. EKB-569 targets the epidermal growth factor receptor, a signaling cascade frequently activated in colon cancers. In this model, low-dose sulindac (5 mg/kg) was ineffective, whereas standard-dose sulindac (20 mg/kg) and EKB-569 caused a significant suppression of intestinal adenomas (by 29% and 87%, respectively). Furthermore, the combination of low-dose sulindac and EKB-569 resulted in a dramatic 96% reduction in tumors. Indeed, complete polyp suppression was evident in half the animals, an outcome that is markedly superior to that of other chemo-
AJG – Vol. 96, No. 2, 2001
preventive agents. However, it is unclear whether EKB-569 and sulindac additive effects are modulated through a common or distinct biological pathway. This report demonstrates the promise of the approach of designing drugs to specifically target the molecular alterations involved in colon cancers. Moreover, it underscores the potential in combinatorial chemopreventive therapy, in which synergy can be obtained at lower doses of individual agents, thus decreasing toxicity. Clinically, this approach, though more efficacious, will increase complexity and expense of chemoprevention. Thus, this strategy may be feasible in only the highest risk patients, although most of the colon cancers occur in “average risk” patients. H. Roy, M.D.
Scoping Inside and Out Franklin ME, Diaz JA, Abrego D, et al. Laparoscopic-assisted colonoscopic polypectomy. Dis Colon Rectum 2000;43:1246 –9. Although colonoscopic polypectomy can be safely performed in the majority of cases, there are patients in whom colonoscopic polypectomy is unsafe or not possible because of the size, location, or nature of the polyp or because of the technical limitations related to the colon (e.g., tortuosity). Operation with colectomy or colotomy to remove such polyps has been recommended when there is a significant risk of malignancy. The laparoscopic approach to colonic disease has been evolving over the past decade. Many polypoid lesions can be removed via this operative approach. A more novel approach to the difficult polyp would be to perform colonoscopic excision under laparoscopic visualization. This would lead to immediate detection of potential problems such as full-thickness injury. Furthermore, if colonoscopic excision is unsuccessful or complicated, immediate
resection or repair could be carried out laparoscopically. The authors report on 60 colonoscopic polypectomies performed in 47 patients by using a combined laparoscopic and colonoscopic approach. The colon was mobilized laparoscopically and colonoscopy performed intraoperatively under direct laparoscopic visualization. Frozen section analysis was carried out to determine the need for resection. The majority of polyps were in the right colon, and 28 of 60 were tubulovillous adenomas. Three malignant polyps were identified; these patients underwent resection laparoscopically. The patients were started on clear liquids 6 h postoperatively and hospitalization averaged 21 h. They returned to full activity after an average of 2 days. There were no significant complications. Thus, this combined approach allows patients to undergo polyp excision without segmental resection and with a recovery time similar to routine colonoscopic polypectomy. J. S. Thompson, M.D., F.A.C.S.
Psychotherapy and Functional Dyspepsia: Brain-Gut Interactions Hamilton J, Guthrie E, Creed F, et al. A randomized controlled trial of psychotherapy in patients with functional dyspepsia. Gastroenterology 2000; 119:661–9. Psychological factors can be identified in many patients with functional bowel disorders (FBDs). Indeed, there are data to suggest that these psychological factors are important contributors to symptoms in FBDs. Psychological therapy could therefore be beneficial to patients with these conditions. Hamilton and colleagues compared the efficacy of psychodynamic-interpersonal (PI) psychotherapy with a psychological control (“supportive therapy”) in patients with chronic symptoms of functional
AJG – February, 2001
dyspepsia who had failed to respond to conventional pharmacological therapy. Seventy-five patients were randomized, observed for psychological and gastrointestinal symptoms, and assessed by intention-to-treat analysis. Forty-nine of them also underwent a radioisotope gastric-emptying test. At the end of the 12-wk course of treatment, gastrointestinal symptom scores were significantly better in the PI group than the controls. Additionally, these symptom improvements were correlated with improvements in psychological symptoms in the PI group alone. One year after treatment, the symptom scores were similar between the two groups; however, a post hoc analysis showed that PI therapy was superior to the control group when patients with severe heartburn were excluded. At the end of treatment and 1 yr later, a reduction in the use of health services was seen in both groups. There was no difference in outcome between patients with normal and those with abnormal gastric emptying. The authors conclude that PI psychotherapy may have both short and long term benefits in patients with chronic, medically unresponsive, functional dyspepsia. Regardless of the generalizability of these results and the lack of clear-cut proof of efficacy, this study was well conceived and conducted and represents the renewed interest in brain-gut interactions in FBDs. Despite the limitations of this study, treatment with psychotherapy of some form remains a promising option, because of the many hints that psychological factors play an important role in FBDs and func-
What’s New in GI
tional dyspepsia in particular. Future studies dealing with selection of an appropriate patient, the appropriate therapy for each patient, and the health economics of this therapy are certainly indicated before widespread implementation can be recommended. J. K. DiBaise, M.D.
One Small Step in Metastatic Colorectal Cancer Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2000;343:905–14. Despite advances in the early detection of colorectal cancer, it remains the second-leading cause of death from cancer in the United States. In most centers, the use of fluorouracil and leucovorin has been the standard first-line therapy for metastatic disease. However, the benefit, though significant, is quite modest. Irinotecan, a topoisomerase I inhibitor, has been shown to be active against colorectal cancer when used either alone as first-line treatment or as a secondline therapy in fluorouracil-based treatment failures. This large multicenter trial from the Irinotecan Study Group compared the use of irinotecan, fluorouracil, and leucovorin (231 patients) with irinotecan alone (226 patients) and the standard bolus regimen of fluorouracil and leucovorin as developed by the Mayo Clinic (226 patients). Baseline characteristics of all three groups were similar except that the
279
proportion of men in the fluorouracil and leucovorin group was slightly lower, 54% versus ⬃65% in the other two treatment groups. With evaluation by an intention-to-treat analysis, statistically significant differences were found in median progressionfree survival (7.0 months vs 4.3 months and 4.2 months), objective response rate (50% vs 28% and 29%), and median overall survival (14.8 months vs 12.6 months and 12.0 months) for irinotecan, fluorouracil, and leucovorin as compared to fluorouracil and leucovorin and irinotecan alone. Over half of the patients in the fluorouracil and leucovorin group received an irinotecan-based drug regimen after the study. Side effects were tolerable, with fluorouracil giving rise to myelosuppression. Diarrhea was the major adverse effect of irinotecan alone (31% grade 3 or 4), although experiences suggest that aggressive prophylactic therapy may mitigate. This study shows a small but significant improvement in overall survival with the use of irinotecan, fluorouracil, and leucovorin for the treatment of metastatic colon cancer. Although the results are modest, given the prevalence of colorectal cancer, this represents a significant clinical advance. Indeed, incremental advances may be the paradigm to make an impact in colorectal cancer survival. This triple-drug regimen will likely become the standard first-line therapy in clinical practice as well as the reference regimen in newly designed phase 3 trials for metastatic colon cancer. R. Brand, M.D.
What’s New in GI
than endoanal MRI. Anal EUS and endoanal MRI have equivalent results in the evaluation of external anal sphincter injury. A. Matamoros, Jr., M.D.
Chemoprevention Adds Up Torrance CJ, Jackson PE, Montgomery E, et al. Combinatorial chemoprevention of intestinal neoplasia. Nat Med 2000;6:1024 – 8. Although a variety of agents protect against colorectal carcinogenesis, their modest efficacy and potential toxicity have limited clinical utility. For example, the cyclo-oxygenase 2–selective nonsteroidal anti-inflammatory drug celecoxib has recently received Food and Drug Administration approval for polyp suppression in familial adenomatous polyposis, although it decreased adenoma number by only one third. Other chemopreventive agents such as ursodeoxycholic acid, calcium, fiber, folate, and estrogens offer a similar 30% to 60%risk reduction. Newer agents are being developed to target specific signaling pathways that are dysregulated during neoplastic transformation. Torrance et al. assess the novel agent EKB-569 alone and in combination with the nonsteroidal anti-inflammatory drug sulindac by utilizing the mouse model of familial adenomatous polyposis. EKB-569 targets the epidermal growth factor receptor, a signaling cascade frequently activated in colon cancers. In this model, low-dose sulindac (5 mg/kg) was ineffective, whereas standard-dose sulindac (20 mg/kg) and EKB-569 caused a significant suppression of intestinal adenomas (by 29% and 87%, respectively). Furthermore, the combination of low-dose sulindac and EKB-569 resulted in a dramatic 96% reduction in tumors. Indeed, complete polyp suppression was evident in half the animals, an outcome that is markedly superior to that of other chemo-
AJG – Vol. 96, No. 2, 2001
preventive agents. However, it is unclear whether EKB-569 and sulindac additive effects are modulated through a common or distinct biological pathway. This report demonstrates the promise of the approach of designing drugs to specifically target the molecular alterations involved in colon cancers. Moreover, it underscores the potential in combinatorial chemopreventive therapy, in which synergy can be obtained at lower doses of individual agents, thus decreasing toxicity. Clinically, this approach, though more efficacious, will increase complexity and expense of chemoprevention. Thus, this strategy may be feasible in only the highest risk patients, although most of the colon cancers occur in “average risk” patients. H. Roy, M.D.
Scoping Inside and Out Franklin ME, Diaz JA, Abrego D, et al. Laparoscopic-assisted colonoscopic polypectomy. Dis Colon Rectum 2000;43:1246 –9. Although colonoscopic polypectomy can be safely performed in the majority of cases, there are patients in whom colonoscopic polypectomy is unsafe or not possible because of the size, location, or nature of the polyp or because of the technical limitations related to the colon (e.g., tortuosity). Operation with colectomy or colotomy to remove such polyps has been recommended when there is a significant risk of malignancy. The laparoscopic approach to colonic disease has been evolving over the past decade. Many polypoid lesions can be removed via this operative approach. A more novel approach to the difficult polyp would be to perform colonoscopic excision under laparoscopic visualization. This would lead to immediate detection of potential problems such as full-thickness injury. Furthermore, if colonoscopic excision is unsuccessful or complicated, immediate
resection or repair could be carried out laparoscopically. The authors report on 60 colonoscopic polypectomies performed in 47 patients by using a combined laparoscopic and colonoscopic approach. The colon was mobilized laparoscopically and colonoscopy performed intraoperatively under direct laparoscopic visualization. Frozen section analysis was carried out to determine the need for resection. The majority of polyps were in the right colon, and 28 of 60 were tubulovillous adenomas. Three malignant polyps were identified; these patients underwent resection laparoscopically. The patients were started on clear liquids 6 h postoperatively and hospitalization averaged 21 h. They returned to full activity after an average of 2 days. There were no significant complications. Thus, this combined approach allows patients to undergo polyp excision without segmental resection and with a recovery time similar to routine colonoscopic polypectomy. J. S. Thompson, M.D., F.A.C.S.
Psychotherapy and Functional Dyspepsia: Brain-Gut Interactions Hamilton J, Guthrie E, Creed F, et al. A randomized controlled trial of psychotherapy in patients with functional dyspepsia. Gastroenterology 2000; 119:661–9. Psychological factors can be identified in many patients with functional bowel disorders (FBDs). Indeed, there are data to suggest that these psychological factors are important contributors to symptoms in FBDs. Psychological therapy could therefore be beneficial to patients with these conditions. Hamilton and colleagues compared the efficacy of psychodynamic-interpersonal (PI) psychotherapy with a psychological control (“supportive therapy”) in patients with chronic symptoms of functional
AJG – February, 2001
dyspepsia who had failed to respond to conventional pharmacological therapy. Seventy-five patients were randomized, observed for psychological and gastrointestinal symptoms, and assessed by intention-to-treat analysis. Forty-nine of them also underwent a radioisotope gastric-emptying test. At the end of the 12-wk course of treatment, gastrointestinal symptom scores were significantly better in the PI group than the controls. Additionally, these symptom improvements were correlated with improvements in psychological symptoms in the PI group alone. One year after treatment, the symptom scores were similar between the two groups; however, a post hoc analysis showed that PI therapy was superior to the control group when patients with severe heartburn were excluded. At the end of treatment and 1 yr later, a reduction in the use of health services was seen in both groups. There was no difference in outcome between patients with normal and those with abnormal gastric emptying. The authors conclude that PI psychotherapy may have both short and long term benefits in patients with chronic, medically unresponsive, functional dyspepsia. Regardless of the generalizability of these results and the lack of clear-cut proof of efficacy, this study was well conceived and conducted and represents the renewed interest in brain-gut interactions in FBDs. Despite the limitations of this study, treatment with psychotherapy of some form remains a promising option, because of the many hints that psychological factors play an important role in FBDs and func-
What’s New in GI
tional dyspepsia in particular. Future studies dealing with selection of an appropriate patient, the appropriate therapy for each patient, and the health economics of this therapy are certainly indicated before widespread implementation can be recommended. J. K. DiBaise, M.D.
One Small Step in Metastatic Colorectal Cancer Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2000;343:905–14. Despite advances in the early detection of colorectal cancer, it remains the second-leading cause of death from cancer in the United States. In most centers, the use of fluorouracil and leucovorin has been the standard first-line therapy for metastatic disease. However, the benefit, though significant, is quite modest. Irinotecan, a topoisomerase I inhibitor, has been shown to be active against colorectal cancer when used either alone as first-line treatment or as a secondline therapy in fluorouracil-based treatment failures. This large multicenter trial from the Irinotecan Study Group compared the use of irinotecan, fluorouracil, and leucovorin (231 patients) with irinotecan alone (226 patients) and the standard bolus regimen of fluorouracil and leucovorin as developed by the Mayo Clinic (226 patients). Baseline characteristics of all three groups were similar except that the
279
proportion of men in the fluorouracil and leucovorin group was slightly lower, 54% versus ⬃65% in the other two treatment groups. With evaluation by an intention-to-treat analysis, statistically significant differences were found in median progressionfree survival (7.0 months vs 4.3 months and 4.2 months), objective response rate (50% vs 28% and 29%), and median overall survival (14.8 months vs 12.6 months and 12.0 months) for irinotecan, fluorouracil, and leucovorin as compared to fluorouracil and leucovorin and irinotecan alone. Over half of the patients in the fluorouracil and leucovorin group received an irinotecan-based drug regimen after the study. Side effects were tolerable, with fluorouracil giving rise to myelosuppression. Diarrhea was the major adverse effect of irinotecan alone (31% grade 3 or 4), although experiences suggest that aggressive prophylactic therapy may mitigate. This study shows a small but significant improvement in overall survival with the use of irinotecan, fluorouracil, and leucovorin for the treatment of metastatic colon cancer. Although the results are modest, given the prevalence of colorectal cancer, this represents a significant clinical advance. Indeed, incremental advances may be the paradigm to make an impact in colorectal cancer survival. This triple-drug regimen will likely become the standard first-line therapy in clinical practice as well as the reference regimen in newly designed phase 3 trials for metastatic colon cancer. R. Brand, M.D.