Support Care Cancer (2007) 15: 1105–1108 DOI 10.1007/s00520-006-0192-9

N. M. A. Blijlevens J. P. Donnelly D. Yakar C. E. van Die T. de Witte

Received: 25 August 2006 Accepted: 8 November 2006 Published online: 5 January 2007 # Springer-Verlag 2007

N. M. A. Blijlevens (*) . J. P. Donnelly . T. de Witte Department of Haematology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 Nijmegen, The Netherlands e-mail: [email protected] Tel.: +31-24-3614762 Fax: +31-24-3542080 D. Yakar . C. E. van Die Department of Radiology, University Medical Centre St. Radboud, Nijmegen, The Netherlands

SH ORT COMMUNI CATIO N

Determining mucosal barrier injury to the oesophagus using CT scan

Abstract Introduction: Oral mucositis is recognised as one of the most debilitating complications of highdose cytostatic chemotherapy used to prepare for haematopoietic stem cell transplantation (HSCT), but very little is known about oesophageal mucositis, as endoscopy is not routinely performed. Materials and methods: We incorporate the computed tomography (CT) scan in the diagnostic workup of fever during neutropenia to detect evidence of pulmonary complications. This allowed us to evaluate whether mucosal barrier injury to the oesophagus can be determined. We selected 46 patients without oesophageal cancer or immune suppression (controls), who had a normal oesophagus, and measured the mucosal thickness at the upper part (UP), middle part (MP) and lower part (LP) of the oesophagus. Next, we selected

Introduction Oral mucositis is the most prominent clinical manifestation of cytotoxic therapy-induced mucosal barrier injury and is the most frequent cause of morbidity associated with the myeloablative regimen to prepare for a haematopoietic stem cell transplantation (HSCT) [6]. Oral mucositis affects almost every HSCT recipient and is easy to recognise by anatomical signs of oedema, ulceration and erythema or by complaints of pain and difficulty in eating or swallowing. Therefore, mucosal damage induced by cytotoxic therapy can be measured either by signs, symptoms or functional changes, all of which are complementary in documenting that injury [4]. The detection of oesophageal mucosal

30 patients having a CT scan done for diagnostic purposes within 14 days after HSCT and measured mucosal thickness at the same levels. We also scored oral mucositis and gut toxicity. Results: The mucosal thickness of the UP, MP and LP, respectively, for the controls (mean ± SD) was 4.1 mm (±1.1), 4.2 mm (±1.2) and 4.8 mm (±1.3), and the corresponding values for the subjects were 5.9 mm (±2.2), 5.9 mm (±2.0) and 7.7 mm (±3.0). Analysis of variance showed statistically significant differences between subjects and controls at all oesophageal levels. All patients suffered from severe oral mucositis at the time. Conclusion: Hence, mucosal barrier injury to the oesophagus can be objectively measured using CT scan. Keywords Mucositis . CT scan . Oesophagus . Mucosal injury

barrier injury is difficult. Symptoms such as heartburn, retrosternal pain or cramps are not specific, and complaints of difficulty in swallowing or eating food are already present due to oral mucositis shortly after transplant. The toxicity scale of the common toxicity criteria (CTC) version 3.0 is not a very good tool because it is not sufficiently specific for documenting oesophageal mucosal injury [9]. Nor are there any other suitable tools available. An alternative means of recognising oesophageal mucosal barrier injury is required if it is to be better understood and managed. Inflammation is the hallmark of cytotoxic therapy-induced mucosal injury and is recognised as oedema or thickening of the mucosa of the whole alimentary tract [1]. Oedema of the mouth can be

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Fig. 1 a Mucosal thickness of oesophagus in control patients. b Mucosal thickness of oesophagus after myeloablative therapy

recognised by inspection and its counterpart in the lower gut by ultrasonography [5]. Endoscopy can be used to detect alterations of the mucosal surface that are features of

oesophageal injury but is not suitable for patients suffering from oral mucositis. A non-invasive method for diagnosing and monitoring oesophageal injury after cytotoxic treat-

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ment would be desirable, but none has been described so far. Computer tomography (CT) might prove valuable in this regard, as it usually forms part of the standard care of HSCT recipients. We had performed CT scanning in a cohort of HSCT recipients for investigating possible invasive fungal disease during febrile neutropenia. We also scored oral mucositis and gut toxicity on a daily basis and thus were given the opportunity of relating any visible changes in the appearance of the oesophageal mucosa temporally with oral mucositis and gut toxicity.

Materials and methods To determine the thickness of a normal oesophagus, we selected a group of patients to serve as a control group. They had undergone CT scanning for other reasons, had no evidence of oesophageal cancer nor were being treated with immune-suppressive medication. We divided the oesophagus into three different parts according to its anatomical structure: an upper part (UP) high in the thoracic area, a middle part (MP) at the level of the carina and a lower part (LP) just above the diaphragm. An appropriate slice from the CT scan made was selected, and the mucosal thickness was measured in millimeter (Fig. 1a). Next, we selected a series of patients who had undergone a CT scan to diagnose possible invasive pulmonary aspergillosis within 14 days after HSCT when mucosal barrier injury is at its worst, peaking around 1 to 2 weeks post-transplant [3]. Mucosal thickness was measured in the same way as for controls and at the same levels (Fig. 1b). We also scored oral mucositis using a daily mucositis score (DMS) and gut toxicity using a daily gut score (DGS) [4]. All patients serologically positive for herpes virus received acyclovir or valaciclovir, but fluconazole at 200 mg per day was given orally only to those shown to be colonized with Candida species other than Candida krusei and Candida glabrata [2]. No haematopoietic growth factors were used. Anti-bacterial prophylaxis consisted of ciprofloxacin, and either cefipime or ceftazidime was administered empirically at the onset of fever. Co-trimoxazole (sulphamethoxazole-trimethoprim) was given for prophylaxis against Pneumocystis jerovici.

Data analysis The mean and standard deviation (SD) of the mucosal thickness of the UP, MP and LP of the controls and patients were compared using analysis of variance (ANOVA). The correlation of the mucosal thickness and DMS of the day of the CT scan was tested using Pearson’s ρ test. If the DMS was not recorded on that specific day, the value from either the day before or after was used. The analysis was performed using SPSS v 11.0 and a p value of <0.05 was considered statistically significant.

Results There were 46 patients who served as controls (18 female, 28 male) with a mean age of 58 years (range 14–85 years) who were evaluated to determine oesophageal mucosal thickness. The mucosal thickness of the UP, MP and LP, respectively, for the controls was 4.1 mm (±1.1), 4.2 mm (±1.2) and 4.8 mm (±1.3). There was no difference between male and female patients (data not shown). Thirty patients (15 female, 15 male) with a mean age of 48 years (range 26–63 years) had received an HSCT after myeloablative therapy to treat a haematological malignancy (acute myeloid leukemia [5], acute lymphocytic leukemia [2], non-Hodgkin lymphoma [1], myelofibroses syndrome [1], myeloproliferative disorder [8], myelofibrosis fungoides [8] or multiple myeloma [6]). Twenty-two of the patients received a human leukocyte antigen (HLA)-matched T cell-depleted transplant from a sibling donor after preparation with idarubicin, given at a dose of 42 mg/m2 by continuous infusion over 48 h starting 12 days before transplant (HSCT day −12), followed by 120 mg/kg cyclophosphamide (60 mg kg−1 day−1 on HSCT days −6 and −5) and 9 Gy of total body irradiation (4.5 Gy day−1 on HSCT days −2 and −1). Eight patients received an autologous HSCT after high-dose melphalan at 100 mg/m2 per day on HSCT days −2 and −1. All patients became profoundly neutropenic (granulocytes<0.1×109/l), but none developed an invasive candidiasis or a Herpes simplex infection. The corresponding values of the UP, MP and LP for the subjects were 5.9 mm (±2.2), 5.9 mm (±2.0) and 7.7 mm (±3.0). ANOVA showed statistically significant differences (p<0.001) between subjects and controls for each part of the oesophagus. At the same time, patients suffered from severe oral mucositis (mean DMS= 8.0±3.0) and gut mucositis (mean DGS=3.0±2.0), but neither oral nor gut mucositis was correlated with mucosal thickness of the oesophagus. Mucosal thickness for each part of the oesophagus was significantly correlated with each other (MP with UP, r=0.65; and LP, r=0.64) but was not different between the two preparative regimens (data not shown). Again, there was no difference between male and female patients or their ages (data not shown). There was no clear pattern of the mucosal thickness with respect to time after transplant because the CT scans were not performed on fixed days; nor was serial CT scanning available.

Discussion Mucositis of the alimentary tract is now recognised as the most debilitating complication of cytotoxic therapy that might be prevented or even treated with specific drugs, and hitherto, guidelines have already been updated [8]. The guidelines offer no advice regarding the treatment of mucosal injury to the oesophagus after myeloablative

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therapy to prepare for HSCT, although amifostine can be used to reduce oesophagitis induced by concomitant chemotherapy and radiotherapy in patients with nonsmall cell lung cancer, and ranitidine or omeprazole is recommended for preventing epigastric pain after treatment with cyclophosphamide, methotrexate and 5FU and treatment with 5FU with or without folinic acid. Dosimetric factors, such as mean radiation dose to the oesophagus, absolute oesophageal volume treated above 15 Gy and the relative volume treated above 10 Gy, primarily determine the severity of treatment-related acute oesophagitis as judged by using three different toxicity scales (CTCv3, Radio Technology and Compatibility Group and M.D. Anderson Cancer Center) among patients treated with induction chemotherapy and three-dimensional conformal radiotherapy for non-small cell lung cancer [11]. Successful intake of food is an important element of these scoring systems in determining the severity of acute oesophagitis but is inappropriate for HSCT recipients with oral mucositis, as oral intake is already poor. Barium swallow, which is used in patients treated for head and neck cancer to assess the safety of oral feeding and the structural integrity of the

pharynx and oesophagus [10], has not been employed for HSCT recipients, and the use of endoscopic optical coherence tomography in combination with Doppler capability may augment imaging of the mucosal and submucosal structures of the oesophagus but is only feasible for patients given less intensive chemo-/radiotherapy [12]. These techniques could be used to investigate the late post-chemotherapy complications like fistulae, which tend to occur after anti-leukaemic treatment [7]. Hence, another clinical tool needs to be developed, one that is easy and relatively safe to use and does not involve endoscopy. Our preliminary results suggest that it might be worthwhile to investigate the utility of diagnosing oesophageal toxicity using serial high-resolution CT scanning after intensive therapy, preferably in a prospective study combining the documentation of the different features of mucosal barrier injury of the oesophagus: signs, symptoms and functional disabilities using endoscopy, CT scanning and selfassessment/quality of life instruments. This would entail measuring each aspect before, during and after intensive cytotoxic therapy in HSCT recipients to describe the course of mucosal damage of the oesophagus.

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