Incidence and risk factors for lower alimentary ... - Wiley Online Library

Original Article

Incidence and Risk Factors for Lower Alimentary Tract Mucositis After 1529 Courses of Chemotherapy in a Homogenous Population of Oncology Patients Clinical and Research Implications Somashekar G. Krishna, MD, MPH1; Weizhi Zhao, MS2; Monica L. Grazziutti, MD2; Naveen Sanathkumar, MD2; Bart Barlogie, MD, PhD2; and Elias J. Anaissie, MD2

BACKGROUND: Lower alimentary tract mucositis is a serious complication of chemotherapy. The aim of the study was to determine the incidence, risk factors, and mortality of lower alimentary tract mucositis in a homogeneous population of patients with newly diagnosed myeloma receiving similar antineoplastic therapy and standardized supportive care. METHODS: Lower alimentary tract mucositis was evaluated among 303 consecutive patients with myeloma (2004-2007) enrolled in a clinical trial consisting of induction chemotherapy, tandem melphalan-based autologous stem cell transplantation (ASCT), and consolidation. Lower alimentary tract mucositis was defined as neutropenia-associated grade II-IV enteritis/colitis. Pretreatment risk factors were examined including body surface area (BSA), serum albumin (albumin), and estimated creatinine clearance (CrCl). Multiple logistic regression model was used to compute adjusted odds ratio (OR) and 95% confidence intervals (CI). RESULTS: Forty-seven (15.5%) patients developed lower alimentary tract mucositis during 1529 courses of chemotherapy (including 536 melphalan-based ASCT). Pre-enrollment BSA 3  106 CD34 cells/kg of body weight.

The diagnosis of neutropenic lower alimentary tract mucositis is not standardized but is usually based on a triad of fever, abdominal pain, and diarrhea, with some authors suggesting the inclusion of radiologically determined bowel wall thickness.5 In a recent systematic review of 21 studies, the authors estimated the incidence of lower alimentary tract mucositis at 5.3% (95% confidence interval [CI], 4.7%-5.9%), with a range of 0.6% to 26%, and attributed this wide variability in incidence to the lack of consensus on definition, the small and nonhomogeneous patient population studied, and low-quality methodologies. The risk factors and mortality of lower alimentary tract mucositis remain poorly defined.5 In this study, we evaluated the incidence, risk factors, and mortality of lower alimentary tract mucositis among a homogeneous and similarly treated population of 303 consecutive newly diagnosed patients with multiple myeloma undergoing 1529 courses of chemotherapy, including high-dose melphalan with autologous hematopoietic stem cell transplantation (ASCT).6 Because we have previously shown that renal dysfunction and body surface area (BSA)-based mg/kg dosing of melphalan were independent risk factors for upper alimentary tract mucositis (oral mucositis) after melphalan-based ASCT,7 we tested the hypothesis whether body measurements (such as BSA) and renal function were also risk factors for lower alimentary tract mucositis.

MATERIALS AND METHODS The study population consisted of adults with newly diagnosed multiple myeloma cared for at the University of Arkansas for Medical Sciences between February 2004 and January 2007. All patients were enrolled in Total Therapy 3, a phase 2 prospective study consisting of 2 Cancer

February 1, 2011

induction courses with multiagent chemotherapy, tandem melphalan-based ASCT, 2 consolidation courses, and maintenance (Table 1).6 Because the maintenance regimen does not cause lower alimentary tract mucositis, this treatment phase was not included in our study. Institutional review board approval was obtained for Total Therapy 3 and for the evaluation of lower alimentary tract mucositis. Patients were managed according to our standards of care including antimicrobial prophylaxis (acyclovir, fluconazole, and levofloxacin) throughout the period of neutropenia, testing for circulating cytomegalovirus (CMV) by polymerase chain reaction8 and therapy with broad spectrum antibiotics (carbapenems or third/fourth generation cephalosporins) for febrile neutropenia and documented bacterial infections. With onset of significant diarrhea,
3 stool samples were tested for Clostridium difficile toxin,9 and computerized axial tomography of abdomen and pelvis was obtained when appropriate. A preemptive approach was taken for managing diarrhea (oral antimotility drugs, intravenous octreotide), dehydration, electrolyte imbalances and deconditioning with early initiation of physical therapy. Nasogastric suctioning and total parenteral nutrition were rarely used. Prophylactic acid suppression therapy was provided during all courses of chemotherapy (histamine 2-receptor antagonists during induction and consolidation; proton pump inhibitors during melphalan-based ASCT). All patients were cared for by clinicians with training and experience in cancer supportive care. The evaluation period started with the first day of chemotherapy for a total of 30 days during the induction and consolidation courses and for 62 days for melphalanbased ASCT (60 days after the infusion of stem cells).6 The last patient follow-up date was January 31, 2007.

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Original Article

Evaluation included daily examination with protocoldefined laboratory studies and other tests as clinically indicated. Adverse events were prospectively collected and graded according to the Common Terminology Criteria for Adverse Events version 3.0 of the National Cancer Institute.10 Lower alimentary tract mucositis was defined as colitis and/or enteritis (grades II-IV) that occurred during chemotherapy-induced neutropenia and in the absence of C. difficile infection. Grade II consisted of abdominal pain and mucus/blood in stool; grade III was defined as abdominal pain, fever, and change in bowel habits with ileus or presence of peritoneal signs, whereas grade IV referred to the development of life-threatening consequences (eg, perforation, bleeding, ischemia, necrosis, or toxic megacolon).10 Neutropenia was defined as absolute neutrophil count