Patients with advanced or recurrent gastrointestinal cancer who underwent fluoropyrimidine-based chemotherapy at Toyama University hospital between April 2006 and June 2017 were retrospectively analyzed. Clinical assessments were repeated every 2 or 3 weeks during chemotherapy, while information was retrospectively collected from medical records. This study was approved by the Institutional Review Board (No. 26-136), and all patients signed an informed consent form prior to participation.
Treatment regimens and schedule
Chemotherapy regimens in clinical practice or within the context of a clinical trial were selected individually. The dosage and schedules of most chemotherapy regimens were based on previously reported recommendations 11, 12. Treatment was continued until disease progression, occurrence of unacceptable toxicity, or patient refusal to continue therapy despite appropriate dose reduction.
Evaluation and management of diarrhea
Diarrhea severity was classified according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4. Complicated diarrhea was defined according to the following American Society of Clinical Oncology guidelines: CTCAE grade 3 or 4 diarrhea or grade 1 or 2 diarrhea with one or more additional signs or symptoms, including cramping, nausea/vomiting (grade 2 or more), decreased performance status, fever, sepsis, neutropenia, frank bleeding, and dehydration 10. Uncomplicated diarrhea was defined as grade 1 or 2 diarrhea with no complicating symptoms.
All patients diagnosed with complicated diarrhea were admitted to the hospital, and their chemotherapy was discontinued. To distinguish between infectious and CID diarrhea, stool cultures (for Clostridium difficile, Escherichia coli, and other infectious agents that cause colitis), complete blood count, electrolyte panel, and computed tomography scans were performed in patients who developed complicated diarrhea. Intravenous fluid and antibiotics were administered until all symptoms had resolved.
Small bowel CE procedure and evaluation
Patients with complicated CID underwent CE when their condition improved to CTCAE grade 1. All patients who underwent CE satisfied the following criteria: (1) no massive ascites or severe peritoneal dissemination; (2) a condition that permitted continued chemotherapy; and (3) oral intake capability.
Depending on each patient’s condition, a patency capsule was used to confirm intestinal patency according to the operator’s discretion. Each patient was instructed not to consume solid food after 8 PM on the day before the procedure. CE studies were performed using the Pillcam™ SB2, SB3 system (Medtronic, Dublin, Ireland) or Endo Capsule™ system (Olympus, Tokyo, Japan). The monitoring period was approximately 10 h, corresponding to the battery life of the device. Two operators classified abnormalities observed in the video as red spots, erosions, and ulcers 13. Red spots were predominantly distinguished from angiectasia based on size. Mucosal erosions and ulcers were classified according to the size of the small bowel mucosal breaks considering that ulcers, by definition, require a degree of penetration and that evaluating lesion depth based on the angle of the image taken by the capsule was often impossible.
The incidence of diarrhea and the number of days from initiation of fluoropyrimidine-based chemotherapy to the onset of complicated CID were investigated. Additionally, time-to-event curves were calculated using the Kaplan–Meier method and compared using the log-rank test. Logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to identify which clinical factors influenced complicated CID. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). More precisely, it is a modified version of R commander designed to add statistical functions frequently used in biostatistics. A p value of <0.05 was considered to indicate statistical significance.