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Diagnosis and Management of Cancer Treatment–Induced Diarrhea
Commentary Diagnosis and Management of Cancer Treatment–Induced Diarrhea Scott Wadler, MD Division of Hematology-Oncology
Department of Oncology Weill Medical College of Cornell University New York, NY
Cancer Treatment–Induced Diarrhea Cancer treatment–induced diarrhea (CTID) remains a major clinical problem for the practicing oncologist. At a general level, it is disruptive to the life of the patient, who often has to adjust his life to have access to a bathroom on a frequent basis and who may be awakened several times a night for nocturnal bowel movements. More specifically, CTID can be associated with fluid and electrolyte loss, intestinal permeability to bacteria, fungal and viral infections, requirements for out-patient or in-patient hydration, cramping and abdominal pain, and impaired quality of life.1 Unlike other chemotoxic effects, such as nausea and vomiting or myelosuppression, there is currently no effective therapy for CTID.
Toxicities Associated with Fluoropyrimidine and Irinotecan Cancer treatment–induced diarrhea is a common problem, but is most closely associated with fluoropyrimidine and irinotecan treatment. There are 2 syndromes associated with excessive deaths in patients being treated with bolus irinotecan-based regimens. One is a vascular syndrome associated with thrombotic and embolic disease, including cerebrovascular accident, acute myocardial infarction, and deep vein thrombosis. The second syndrome is a gastrointestinal syndrome defined by diarrhea, cramps, nocturnal stools, and sepsis.2 Management of these syndromes remains a serious clinical problem. In a study of excessive deaths in a pair of clinical trials—one adjuvant and one for advanced disease—it was found that the syndrome was undermanaged, and in general this occurred at institutions that treated large numbers of patients. The other pertinent observation is that, at least among the patients on the adjuvant study, it is likely that some of the excessive
382 • Clinical Colorectal Cancer March 2005
deaths occurred among patients who were cured. Therefore, greater attention to the management of this syndrome is required.
Toxicities Associated with Other Chemotherapeutic Agents Other drugs also appear to play a role in causing CTID. In a recent study of 5fluorouracil (5-FU)/leucovorin (LV) plus oxaliplatin versus 5-FU/LV alone (NSABP C-07), there was an increase in CTID among patients receiving combination therapy, despite the fact that oxaliplatin does not cause significant CTID by itself.3 The outcomes that were measured included bowel wall injury plus hospitalization, which increased from 3.3% to 5.9%; severe or life-threatening diarrhea plus sepsis, which increased from 0.6% to 1.9%; and deaths, which increased from 0 to 5. In one trial with 420 patients, the incidence of grade 3/4 diarrhea increased from 5% in patients receiving 5FU/LV to 12% in patients receiving 5FU/LV plus oxaliplatin.4 In a trial employing oxaliplatin with a bolus 5-FU regimen, the incidence of grade 3/4 diarrhea was 29% (n = 42),5 and in a trial of capecitabine/oxaliplatin, the incidence of grade 3/4 diarrhea was 44%.6
Management of Cancer Treatment–Induced Diarrhea The management of CTID has been discussed thoroughly by O’Brien et al in this issue of Clinical Colorectal Cancer.7 There are several important points that deserve further emphasis. The first point is that CTID is underdiagnosed. It is important to query patients on a weekly or biweekly basis as to what symptoms they are having. Furthermore, for patients with diarrhea, it is important to ask about the number of bowel movements, the consistency of the stool, nocturnal stools, cramping, fevers, chills, and vomiting. The second point is that CTID is undermanaged. Many of the patients in the Cancer and Leukemia Group B study who died had received insufficient antidiarrheal therapy and were underhydrated. Additional antibiotic therapy was also warranted. Unlike other supportive therapies, the treatment of CTID has been short of
successful. Even effective therapies such as octreotide acetate have a limited role because they require injection. The longacting form of octreotide acetate is of interest; however, it requires an intramuscular injection and, more importantly, it does not start to work for 7 days. The delay in action for this compound makes it less than effective as a therapy for acute disease, although there is potential for this agent as a prophylactic therapy in patients who developed diarrhea during the course of their therapy. In a recent randomized phase II trial in which octreotide 30 mg was compared with octreotide 40 mg, therapy was well tolerated in both arms, and, predictably, there was little difference in clinical outcomes or toxicities between the 2 arms. One novel area that is just beginning to be explored is the use of probiotic agents in the treatment of diarrhea. Probiotics are live organisms that run interference between pathogens such as Escherichia coli and the gut wall.8 These agents bind to normal cells and prevent the binding of pathogenetic organisms.9 The mechanisms of action of these agents are complex and involve interactions with the gut and with other microorganisms in the gut.10 Furthermore, probiotics may be involved in transmembrane signaling of MUC2 and possibly other molecules.11,12 In a randomized clinical trial with 206 patients, lactobacillius cultures were effective in reducing radiation-induced diarrhea.13 Several additional points are addressed by O'Brien et al.7 One issue is that of patient education, which deserves strong emphasis for several reasons. Education empowers the patient to take at least partial responsibility for his own care. This requires a good network of communications between patient and physician. Patients very much appreciate being part of the process of their own care and can be helpful to the physician and clinical staff. The second issue is management of CTID. This is also addressed well, focusing on the management guidelines developed by Benson et al.14 These guidelines may be very useful to the practicing physician who has to manage CTID on a weekly basis. The clear innovation in this update of the previous article on the same subject
is the early division of patients into complicated and uncomplicated. All other management decisions sort out well once this initial choice is made.
3.
Conclusion In summary, the article by O'Brien et al is a useful addition to the literature on CTID. The emphasis on patient-related issues, such as patient education, as well as on more technical subjects (ie, pathophysiology) gives the review a broad appeal and wide audience. This article also reveals, however, that further work is necessary in this field. 1. Wadler S, Benson AB III, Engelking C, et al. Recommended guidelines for the treatment of chemotherapy-induced diarrhea. J Clin Oncol 1998; 16:3169-3178. 2. Rothenberg ML, Meropol NJ, Poplin EA, et al.
4.
5.
6.
7.
8.
Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: summary findings of an independent panel. J Clin Oncol 2001; 19:3801-3807. Smith R, Colangelo S, Weiand JP, et al. The occurrence of severe enteropathy among patients with stage II/III resected colon cancer (CC) treated with 5-FU/leucovorin (FL) plus oxaliplatin (FLOX). Proc Am Soc Clin Oncol 2003; 22:294 (Abstract #1181). de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18:2938-2947. Hochster H, Chachoua A, Speyer J, et al. Oxaliplatin with weekly bolus fluorouracil and low-dose leucovorin as first-line therapy for patients with colorectal cancer. J Clin Oncol 2003; 2:2703-2707. Scheithauer W, Kornek GV, Raderer M, et al. Intermittent weekly high-dose capecitabine in combination with oxaliplatin: a phase I/II study in first-line treatment of patients with advanced colorectal cancer. Ann Oncol 2002; 13:1583-1589. O'Brien B, Kaklamani V, Benson AB. The assessment and management of cancer treatment–related diarrhea. Clin Colorectal Cancer 2005; 4:375-381. Lievin-Le Moal V, Amsellem R, Servin AL, et al.
9. 10.
11.
12.
13.
14.
Lactobacillus acidophilus (strain LB) from the resident adult human gastrointestinal microflora exerts activity against brush border damage promoted by a diarrhoeagenic Escherichia coli in human enterocyte-like cells. Gut 2002; 50:803-811. Gorbach SL. Lactic acid bacteria and human health. Ann Med 1990; 22:37-41. Kailasapathy K, Chin J. Survival and therapeutic potential of probiotic organisms with reference to Lactobacillus acidophilus and Bifidobacterium spp. Immunol Cell Biol 2000; 78:80-88. Mattar AF, Coran AG, Teitelbaum DH. MUC-2 mucin production in Hirschsprung’s disease: possible association with enterocolitis development. J Pediatr Surg 2003; 38:417-421 Mattar AF, Teitelbaum DH, Drongowski RA, et al. Probiotics up-regulate MUC-2 mucin gene expression in a Caco-2 cell-culture model. Pediatr Surg Int 2002; 18:586-590. Urbancsek H, Kazar T, Mezes I, et al. Results of a double-blind, randomized study to evaluate the efficacy and safety of Antibiophilus in patients with radiation-induced diarrhoea. Eur J Gastroenterol Hepatol 2001; 13:391-396. Benson AB III, Ajani JA, Catalano RB, et al. Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol 2004; 22:2918-2926.
Clinical Colorectal Cancer March 2005
• 383
Department of Oncology Weill Medical College of Cornell University New York, NY
Cancer Treatment–Induced Diarrhea Cancer treatment–induced diarrhea (CTID) remains a major clinical problem for the practicing oncologist. At a general level, it is disruptive to the life of the patient, who often has to adjust his life to have access to a bathroom on a frequent basis and who may be awakened several times a night for nocturnal bowel movements. More specifically, CTID can be associated with fluid and electrolyte loss, intestinal permeability to bacteria, fungal and viral infections, requirements for out-patient or in-patient hydration, cramping and abdominal pain, and impaired quality of life.1 Unlike other chemotoxic effects, such as nausea and vomiting or myelosuppression, there is currently no effective therapy for CTID.
Toxicities Associated with Fluoropyrimidine and Irinotecan Cancer treatment–induced diarrhea is a common problem, but is most closely associated with fluoropyrimidine and irinotecan treatment. There are 2 syndromes associated with excessive deaths in patients being treated with bolus irinotecan-based regimens. One is a vascular syndrome associated with thrombotic and embolic disease, including cerebrovascular accident, acute myocardial infarction, and deep vein thrombosis. The second syndrome is a gastrointestinal syndrome defined by diarrhea, cramps, nocturnal stools, and sepsis.2 Management of these syndromes remains a serious clinical problem. In a study of excessive deaths in a pair of clinical trials—one adjuvant and one for advanced disease—it was found that the syndrome was undermanaged, and in general this occurred at institutions that treated large numbers of patients. The other pertinent observation is that, at least among the patients on the adjuvant study, it is likely that some of the excessive
382 • Clinical Colorectal Cancer March 2005
deaths occurred among patients who were cured. Therefore, greater attention to the management of this syndrome is required.
Toxicities Associated with Other Chemotherapeutic Agents Other drugs also appear to play a role in causing CTID. In a recent study of 5fluorouracil (5-FU)/leucovorin (LV) plus oxaliplatin versus 5-FU/LV alone (NSABP C-07), there was an increase in CTID among patients receiving combination therapy, despite the fact that oxaliplatin does not cause significant CTID by itself.3 The outcomes that were measured included bowel wall injury plus hospitalization, which increased from 3.3% to 5.9%; severe or life-threatening diarrhea plus sepsis, which increased from 0.6% to 1.9%; and deaths, which increased from 0 to 5. In one trial with 420 patients, the incidence of grade 3/4 diarrhea increased from 5% in patients receiving 5FU/LV to 12% in patients receiving 5FU/LV plus oxaliplatin.4 In a trial employing oxaliplatin with a bolus 5-FU regimen, the incidence of grade 3/4 diarrhea was 29% (n = 42),5 and in a trial of capecitabine/oxaliplatin, the incidence of grade 3/4 diarrhea was 44%.6
Management of Cancer Treatment–Induced Diarrhea The management of CTID has been discussed thoroughly by O’Brien et al in this issue of Clinical Colorectal Cancer.7 There are several important points that deserve further emphasis. The first point is that CTID is underdiagnosed. It is important to query patients on a weekly or biweekly basis as to what symptoms they are having. Furthermore, for patients with diarrhea, it is important to ask about the number of bowel movements, the consistency of the stool, nocturnal stools, cramping, fevers, chills, and vomiting. The second point is that CTID is undermanaged. Many of the patients in the Cancer and Leukemia Group B study who died had received insufficient antidiarrheal therapy and were underhydrated. Additional antibiotic therapy was also warranted. Unlike other supportive therapies, the treatment of CTID has been short of
successful. Even effective therapies such as octreotide acetate have a limited role because they require injection. The longacting form of octreotide acetate is of interest; however, it requires an intramuscular injection and, more importantly, it does not start to work for 7 days. The delay in action for this compound makes it less than effective as a therapy for acute disease, although there is potential for this agent as a prophylactic therapy in patients who developed diarrhea during the course of their therapy. In a recent randomized phase II trial in which octreotide 30 mg was compared with octreotide 40 mg, therapy was well tolerated in both arms, and, predictably, there was little difference in clinical outcomes or toxicities between the 2 arms. One novel area that is just beginning to be explored is the use of probiotic agents in the treatment of diarrhea. Probiotics are live organisms that run interference between pathogens such as Escherichia coli and the gut wall.8 These agents bind to normal cells and prevent the binding of pathogenetic organisms.9 The mechanisms of action of these agents are complex and involve interactions with the gut and with other microorganisms in the gut.10 Furthermore, probiotics may be involved in transmembrane signaling of MUC2 and possibly other molecules.11,12 In a randomized clinical trial with 206 patients, lactobacillius cultures were effective in reducing radiation-induced diarrhea.13 Several additional points are addressed by O'Brien et al.7 One issue is that of patient education, which deserves strong emphasis for several reasons. Education empowers the patient to take at least partial responsibility for his own care. This requires a good network of communications between patient and physician. Patients very much appreciate being part of the process of their own care and can be helpful to the physician and clinical staff. The second issue is management of CTID. This is also addressed well, focusing on the management guidelines developed by Benson et al.14 These guidelines may be very useful to the practicing physician who has to manage CTID on a weekly basis. The clear innovation in this update of the previous article on the same subject
is the early division of patients into complicated and uncomplicated. All other management decisions sort out well once this initial choice is made.
3.
Conclusion In summary, the article by O'Brien et al is a useful addition to the literature on CTID. The emphasis on patient-related issues, such as patient education, as well as on more technical subjects (ie, pathophysiology) gives the review a broad appeal and wide audience. This article also reveals, however, that further work is necessary in this field. 1. Wadler S, Benson AB III, Engelking C, et al. Recommended guidelines for the treatment of chemotherapy-induced diarrhea. J Clin Oncol 1998; 16:3169-3178. 2. Rothenberg ML, Meropol NJ, Poplin EA, et al.
4.
5.
6.
7.
8.
Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: summary findings of an independent panel. J Clin Oncol 2001; 19:3801-3807. Smith R, Colangelo S, Weiand JP, et al. The occurrence of severe enteropathy among patients with stage II/III resected colon cancer (CC) treated with 5-FU/leucovorin (FL) plus oxaliplatin (FLOX). Proc Am Soc Clin Oncol 2003; 22:294 (Abstract #1181). de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18:2938-2947. Hochster H, Chachoua A, Speyer J, et al. Oxaliplatin with weekly bolus fluorouracil and low-dose leucovorin as first-line therapy for patients with colorectal cancer. J Clin Oncol 2003; 2:2703-2707. Scheithauer W, Kornek GV, Raderer M, et al. Intermittent weekly high-dose capecitabine in combination with oxaliplatin: a phase I/II study in first-line treatment of patients with advanced colorectal cancer. Ann Oncol 2002; 13:1583-1589. O'Brien B, Kaklamani V, Benson AB. The assessment and management of cancer treatment–related diarrhea. Clin Colorectal Cancer 2005; 4:375-381. Lievin-Le Moal V, Amsellem R, Servin AL, et al.
9. 10.
11.
12.
13.
14.
Lactobacillus acidophilus (strain LB) from the resident adult human gastrointestinal microflora exerts activity against brush border damage promoted by a diarrhoeagenic Escherichia coli in human enterocyte-like cells. Gut 2002; 50:803-811. Gorbach SL. Lactic acid bacteria and human health. Ann Med 1990; 22:37-41. Kailasapathy K, Chin J. Survival and therapeutic potential of probiotic organisms with reference to Lactobacillus acidophilus and Bifidobacterium spp. Immunol Cell Biol 2000; 78:80-88. Mattar AF, Coran AG, Teitelbaum DH. MUC-2 mucin production in Hirschsprung’s disease: possible association with enterocolitis development. J Pediatr Surg 2003; 38:417-421 Mattar AF, Teitelbaum DH, Drongowski RA, et al. Probiotics up-regulate MUC-2 mucin gene expression in a Caco-2 cell-culture model. Pediatr Surg Int 2002; 18:586-590. Urbancsek H, Kazar T, Mezes I, et al. Results of a double-blind, randomized study to evaluate the efficacy and safety of Antibiophilus in patients with radiation-induced diarrhoea. Eur J Gastroenterol Hepatol 2001; 13:391-396. Benson AB III, Ajani JA, Catalano RB, et al. Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol 2004; 22:2918-2926.
Clinical Colorectal Cancer March 2005
• 383