J Gastrointest Canc DOI 10.1007/s12029-017-9955-4
CASE REPORT
Two Cases of Capecitabine-Induced Ileitis in Patients Treated with Radiochemotherapy to the Pelvis and Review of the Literature L. Nicosia 1
&
I. Russo 1 & V. De Sanctis 1 & G. Minniti 2 & M. Valeriani 1 & M. F. Osti 1
# Springer Science+Business Media New York 2017
Introduction
Case Report 1
Colorectal cancer is the third most common cancer in the Western World. Locally advanced disease is treated with a preoperative approach with the purpose to improve local control and to make possible a sphincter saving surgery. Preoperative treatment mainly consists of RT alone (short-course) or RCT (long-course) [1, 2]; in the concomitant strategy, RT is usually associated with capecitabine, an oral fluoropyrimidine that is a prodrug of 5fluoruracil. The most common side effects of capecitabine include nausea, vomiting, hand-foot syndrome, and mucositis. Serious adverse effects are bowel obstruction and perforation [3]. It is proven the higher incidence of gastrointestinal toxicity in patients treated with RCT respect the sole RT [1, 2]; in particular, concomitant administration of 5-FU lead to a significant increase in G ≥ 2 diarrhea. We report two cases of ileitis in two patients affected by locally advanced rectal cancer treated with preoperative RCT and concomitant capecitabine. A review of the literature shows only one other case of this rare capecitabine-related side effect during pelvic irradiation [4].
After the appearance of rectal bleeding, a 71-year-old woman underwent a colonoscopy that documented an ulcerative and vegetative lesion at 40 mm from the anal verge with reduction of 1/4 of the lumen of the rectum and a cranio-caudal extension of 40 mm. The biopsy specimen demonstrated the presence of an adenocarcinoma. Pelvic RM and total body CT scan documented a locally advanced adenocarcinoma of the rectum (cT3 cN1). Patient was therefore candidate for a preoperative radiochemotherapy. Radiotherapy was delivered by a LINAC using 6 MV energy photons, treatment was planned using a IMRT-SIB technique, and daily cone-beam (Kilo-Voltage) CT was performed to control position (IGRT). The dose to the rectum and mesorectum was 55 Gy in 25 fractions of 2.2 Gy, 5 days/ week; the total dose to pelvic lymphnodes (including bilateral common iliac and internal iliac, presacral, obturators) was 45 Gy in 25 fraction of 1.8 Gy. Concomitant chemotherapy consisted of daily capecitabine 825 mg/mq bid, d1–25. At the 16th fraction, patient developed severe diarrhea (grade 3), abdominal pain, vomiting (grade 2), and handfoot syndrome (grade 3). Patient was admitted to the Emergency Department with a severe state of dehydration. IV fluids and electrolytes were promptly administered. A CT scan of the abdomen and pelvis documented a diffuse edema of the distal ileum with important reduction of the lumen and distended loop of the small bowel (Fig. 1b). Combined treatment was interrupted. During the hospitalization, patient also experienced fever treated with wide-spectrum antibiotics; with these intervention conditions gradually improved and after 15 days, patient was dismissed by the hospital and was able to restart the sole radiotherapy without any other interruptions. The final diagnosis was ileitis.
* L. Nicosia
[email protected]
1
Department of Radiation Oncology, Sant’Andrea Hospital, BSapienza^ University of Rome, via di Grottarossa 1036-38, 00168 Rome, Italy
2
IRCCS Neuromed, Pozzilli, IS, Italy
J Gastrointest Canc
Fig. 1 a Case 1, planning CT. Axial view showing bowel loops included in the 45Gy isodose level (white line). b Case 1, computer tomography scan fused with treatment plan. Axial view showing edema and tickening
of the ileum wall and small bowel distension. The 45Gy isodose level is identified by the white line
Capecitabine was not resumed. Hand-foot syndrome recovered after other 15 days.
RCT with capecitabine. In the literature, eight other cases are reported of capecitabine-induced ileitis but none of them occurred during concomitant treatment, as shown in Table 1. Capecitabine is absorbed by the gastrointestinal tract and is metabolized by three enzymes into 5-fluoruracil, the active principle. Advantages of capecitabine are oral administration and good tolerance. Side effects during capecitabine appear to be dose-dependent and schedule-dependent; the majority of these can be managed with drug interruption or dose reduction; nevertheless, some effects can be life threatening and can require hospitalization and invasive procedures. All the cases reported in the literature occurred during the first 4 cycles of palliative chemotherapy, where the dose of capecitabine is usually higher respect the dose used concomitant with RT, sometimes in patients previously treated with the drug [4–9]. Common symptoms of ileitis were severe diarrhea and abdominal pain. CT scan is a helpful tool due its ability to detect edema and distension of the small bowel, typical presentation of this condition (Figs. 1b and 2b). The management of capecitabine-ileitis consists of immediate interruption of capecitabine and conservative treatment of the symptoms, such as hydration and total parenteral nutrition. It is recommended to start prophylactic broad-spectrum antibiotic coverage. After the resolution of the ileitis, two cases have been reported of well-tolerated rechallenge of capecitabine at reduced dose [7].
Case Report 2 A 54-year-old woman affected by a locally advanced cancer of the lower rectum, cT3 cN0 was admitted to our Department to receive a preoperative RCT with concomitant capecitabine. Concomitant treatment was delivered as reported in case 1. Patient completed the entire course of treatment without interruption and was dismissed with abdominal pain and diarrhea G2; conservative treatment was prescribed at home. Few days after the dismission, symptoms worsened and patient was hospitalized with sub-occlusion, severe abdominal pain, and dehydration. A CT scan of the abdomen showed distended bowel loops with edematous thickening of the ileum and perivisceral effusion (Fig. 2b). Treatment consisted of IV hydration and nutrition, bowel rest, and wide-spectrum antibiotics. With these intervention symptoms, patient recovered in 7 days and at the 12th day, patient was dismissed by the hospital in good clinical conditions.
Discussion We presented two cases of ileitis occurred in patients affected by locally advanced rectal cancer, treated with concomitant
Fig. 2 a Case 2, treatment planning CT. Axial view showing bowel loops included in the boost field (white arrow heads). White line: 45 Gy isodose level. b Case 2, computer tomography scan fused with treatment plan.
Axial view showing edematous tickening of the bowel loops outside of the treatment field. White line: 45 Gy isodose level
Case 8, • 54-year-old man Barton [9] • Colon adenocarcinoma • Adjuvant capecitabine Case 9, • 71-year-old woman Nicosia
• 73-year-old man Case 4, • Metastatic colon cancer Bouma and Imholz • Capecitabine, oxaliplatin and bevacizumab as [7] palliative intent Case 5, Lee • 61-year-old woman [8] • Metastatic colon cancer • Capecitabine, irinotecan and Bevacizumab as palliative intent Case 6, Lee • 59-year-old woman [8] • Sigmoid colon cancer • Adjuvant capecitabine
Case 3, Radawan [6]
• 67-year-old woman • Metastastic triple negative breast cancer • Capecitabine as palliative intent • 67-year-old man • Colon adenocarcinoma • Adjuvant capecitabine
C3D14
2500 mg/mq q21
825 mg/mq bid d1–25 16th fraction
C3
C4D9
Not reported
Not available
End of C3
C2D16
C2D2
Not reported
C1: 1000 mg/mq bid (20% dose initial reduction) C2: 1250 mg/mq bid
Not reported
Severe cramps, diarrhea
Mucositis G3, hand-foot-skin reaction, diarrhea G4, severe generalized abdominal pain (also febrile neutropenia)
Right lower quadrant abdominal pain, watery diarrhea, vomiting (also neutropenia G3 and hypokaliemia)
Abdominal pain, nausea, diarrhea with subfrebile temperature
Diarrhea G3, reduced appetite, lower abdominal discomfort, giddiness
Diarrhea, fever, fatigue and reduced appetite
Diarrhea, fever, fatigue, emesis
C1D15
Case 2, Mokrim [5]
Fever, abdominal pain, diarrhea and vomiting
C1D12
• 67-year-old man 1500 mg bid d1–14, Case 7, q21 Al-Gahmi • Metastatic rectal cancer • Pelvic radiotherapy (3Gy × [4] 10) • XELOX (sequential to RT) • 66-year-old woman 1250 mg/mq bid Case 1, Mokrim • Metastastic ductal breast cancer [5] • Capecitabine as palliative intent
Clinical details
Time to event
Patient
Case reports of capecitabine-related ileitis in the literature Dose of capecitabine
Table 1
• IVantibiotics wide spectrum • IV hydration
• Abdominal CT: diffuse edema of the distal ileum with important
• Colonscopy: ulcerative ileitis • Histopathology: eosinophilic infiltrate
• Total parental nutrition • Inotropic support • Electrolyte replacement • Antibiotics broad spectrum • Not specified if capecitabine restart • Parenteral nutrition • Empiric antibiotics
• Adaptive diet • IV hydration • Capecitabine interruption (restart after 4 weeks at reduced dose) • IV hydration • Antibiotics broad spectrum • Capecitabine permanent interruption
• IVantibiotics wide spectrum • symptomatic management • Capecitabine permanent interruption
• IVantibiotics wide spectrum • Hydratation • bowel rest • Capecitabine permanent interruption
• IV antibiotics • IV hydration • Capecitabine interruption (restart after 5 weeks at reduced dose) • Antibiotics • Hydratation • Capecitabine permanent interruption
Management
• Abdominal CT: diffuse submucosal edema of a long segment of the distal ileum with surrounding stranding. Multiple gas bubble along the wall of the edematous distal ileum (pneumatosis intestinalis)
• Abdominal CT: submucosal edema at the terminal and middle part of the ileum, adjacent increase in fat stranding
• Abdominal X-ray: distended loops of small bowel • Abdominal CT: fluid distended loops of small bowel with abnormal tickening and inflammatory changes of the wall of the distal loops of ileum • Abdominal CT: bowel wall tickening (particularly of the ileum)
• Abdominal CT: submucosal oedema of the distal ileum with abdominal thickening of its wall • Colonscopy with biopsy: eosinophilic infiltrates confirming the diagnosis of ileitis • DPD mutation: positive • Abdominal CT: parietal tickening of the terminal ileal loop • DPD mutation: negative
• Colonscopy: isolated ulceration of the terminal ileum • Histopathology: eosinophilic infiltrate • DPD mutation: negative
Diagnostics
J Gastrointest Canc
• IV hydration and nutrition • Bowel rest • Wide-spectrum antibiotics • Abdominal CT: distended bowel loops with edematous thickening of the ileum and perivisceral effusion Case 10, Nicosia
DPD dihydropyrimidine dehydrogenase
825 mg/mq bid d1–25 3 days after Sub-occlusion, severe abdominal the end of pain, dehydration RCT
• Capecitabine permanent interruption (continue RT alone) reduction of the lumen; distended loop of the small bowel Diarrhorea G3, vomiting G2, severe abdominal pain, hand-foot syndrome G3
• Rectal adenocarcinoma cT3 cN1 • Preoperative RCT (concomitant capecitabine) • 54-year-old woman • Rectal adenocarcinoma cT3 cN0 • Preoperative RCT (concomitant capecitabine)
Patient
Table 1 (continued)
Dose of capecitabine
Time to event
Clinical details
Diagnostics
Management
J Gastrointest Canc
Patients presented in this report developed ileitis during concomitant RCT. Considering the low dose of capecitabine administered during concomitant treatment, we hypothesized that RT played a role as cofactor in the development of the ileitis. IMRT is widely accepted as standard technique to treat rectal cancer. Two dosimetric studies demonstrated that IMRT significantly reduce the volume of organs at risk (OAR) that receive high dose (bladder, femoral heads and small bowel) [10, 11]. We analyzed the planning CT and the Dose-Volume Histogram (DVH) of the IMRT plan of patient 1: contouring as OAR the bowel bag (volume of abdominal cavity containing small bowel loops) we noted that constraints were respected. We noted, also, that some bowel loops were adherent to the uterus, despite patient did not received abdominal surgery in her past history; therefore, we contoured as OAR the bowel loops calculating the constraints, as reported in the literature [12]. Some values were out of range: V15 = 231 cm3 (V15 ≤ 150 cm3), V45 = 192.5 cm3 (V45 ≤ 80 cm3), and V50 = 175 cm3 (V50 ≤ 20 cm3). Then, we fused the pre-treatment planning CT with the CT during hospitalization, finding that in the area with edematous and distended bowel loops constraints were not respected (Fig. 1). But the toxicity arose when the mean dose delivered to small bowel was 27.6 Gy and radiotherapy may have played only a role of cofactor respect to the capecitabine; in addition, the patient presented hand-foot syndrome G3, that might suggest a hypersensitivity to the drug. Patient 2 presented some bowel adherence and a history of cesarean operations. Some bowel loops were located between mesorectum and uterus and received the boost total dose (55 Gy) (Fig. 2a). Sparing this structure was not possible, at the time of contouring, for the risk of underdosage of mesorectum (primary volume of treatment) with possible reduction of treatment efficacy. In the case reported by Al-Gahmi et al. [4], patient also received pelvic palliative irradiation, but the authors themselves concluded that RT was not likely to be the cause of the ileitis as the field of radiation exposure was away from the terminal ileum, the toxicity occurred 6 weeks after the end of the RT, the dose of RT was relatively low (30 Gy in 10 fractions), and the symptoms correlated with the dose of capecitabine. To our knowledge, these are the first two cases reported in the literature of ileitis during concomitant RCT. Ileitis can be a life-threatening toxicity, early identification and promptly treatment are necessary, and therefore clinicians should be aware of this condition.
Conclusion The cases reported in this paper are the first in the literature of ileitis during concomitant RCT with capecitabine. Capecitabine is the major responsible of this toxicity. Despite modern
J Gastrointest Canc
radiotherapy techniques allow to spare organs at risk and to safely deliver treatment, we focused the attention on the importance of the respect of the constraint contouring bowel loops. Nevertheless, in patients with particular anatomical variations may be difficult to respect constraints for the risk of an eventual underdosage of target. Early identification of symptoms is essential to administer a conservative therapy and to complete the radiation treatment after the resolution of the condition.
5.
6.
7.
8.
9.
References 1.
2.
3.
4.
Mohiuddin M, Marks J, Marks G. Management of rectal cancer: short vs. long-course preoperative radiation. Int J Radiat Oncol Biol Phys. 2008;72:636. Kim JS, Kim JS, Cho MJ, Song KS, Yoon WH. Preoperative chemoradiation using oral capecitabine in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2002;54:403. Saif MW, Katirtzoglou NA, Syrigos KN. Capecitabine: an overview of the side effects and their management. Anti-Cancer Drugs. 2008;19:447–64. Al-Gahmi AM, Kerr IG, Zekri JM, Zagnoon AA. Capecitabineinduced terminal ileitis. Ann Saudi Med. 2012;32:661–2.
10.
11.
12.
Mokrim M, Aftimos PG, Errihani H, Piccart-Gebhart M. Breast cancer, DPYD mutations and capecitabine-related ileitis: description of two cases and a review of the literature. BMJ Case Rep. 2014; doi:10.1136/bcr-2014-203647. Radwan R, Namelo WC, Robinson M, Brewster AE, Williams GL. Ileitis secondary to oral capecitabine treatment? Case Rep Med. 2012;2012:154981. Bouma G, Imholz AL. Ileitis following capecitabine use Nederlands Tijdschrift voor Geneeskunde, vol. 155, article A3064, 2011. Lee SF, Chiang CL, Lee AS, Wong FC, Tung SY. Severe ileitis associated with capecitabine: two case reports and review of the literature. Mol Clin Oncol. 2015;3(6):1398–400. Barton D. Ulcerative ileitis secondary to adjuvant capecitabine for colon cancer: a case report. (UICC world Cancer Congress 2006). Arbea L, Ramos LI, Martínez-Monge R, Moreno M, Aristu J. Intensity-modulated radiation therapy (IMRT) vs. 3D conformal radiotherapy (3DCRT) in locally advanced rectal cancer (LARC): dosimetric comparison and clinical implications. Radiat Oncol. 2010;5:17. Zhao J, Hu W, Cai G, Wang J, Xie J, Peng J, et al. Dosimetric comparisons of VMAT, IMRT and 3DCRT for locally advanced rectal cancer with simultaneous integrated boost. Oncotarget. 2016;7(5):6345–51. Zhu J, Liu F, Weilie G, Lian P, Sheng W, Xu J, et al. Concomitant boost IMRT-based neoadjuvant chemoradiotherapy for clinical stage II/III rectal adenocarcinoma: results of a phase II study. Radiat Oncol. 2014;9:70. doi:10.1186/1748-717X-9-70.
