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In this case series, three consecutive patients with unresectable locally advanced pancreatic cancer (ULAPC) underwent capsule endoscopy (CE) before and after chemoradiotherapy (CRT) to evaluate duodenal and jejunal mucosa, and to examine the relationship between CE findings and dose distribution. CE after CRT showed duodenitis and proximal jejunitis in all three patients. The most inflamed region was the third part of the duodenum, and in dose distribution, this was the closest region to the center of irradiation. This case series shows that CE can safely diagnose acute duodenitis and proximal jejunitis caused by CRT for ULAPC, and that dose distribution is possible to predict the degree of duodenal and jejunal mucosal injuries.
In patients with unresectable locally advanced pancreatic cancer (ULAPC), chemoradiotherapy (CRT) is one of the effective standard therapies . Despite the increasing numbers of cases of pancreatic cancer and patients undergoing radiotherapy (RT), there are only a few reports on the adverse gastrointestinal effects, especially radiation enteritis (RE).
From August to November 2014, three patients (patient A is a male in his 60’s; patient B is a female in her 70’s; and patient C is a male in his 60’s) with ULAPC in the head of the pancreas were treated at our hospital. All three patients provided written informed consent on all procedures associated with the study. The patient characteristics and lesions are shown in Table 1. Patient A received 1000 mg/m2 gemcitabine, and patients B and C received 1000 mg/m2 gemcitabine plus 100 mg/m2 nab-paclitaxel intravenously beginning on the first day of RT, then weekly thereafter during radiation. The radiation dose was 1.8 Gy/day, 5 days per week, with a total dose of 50.4 Gy administered in 28 fractions over 5.5 weeks using 10 MV X-rays. Three-dimensional conformal RT was used at five different portals. Gross tumor volume (GTV) was contoured at both expiration and inspiration phases on computed tomography simulation. Clinical target volume (CTV) included GTV with 5-mm margins and planning target volume included CTV with 5-mm margins (Fig. 1). During treatment, all three patients tried to avoid using non-steroidal anti-inflammatory drugs to prevent non-steroid anti-inflammatory drug-caused ulcers. Evaluation of the entire small intestine was carried out immediately before and immediately after CRT. CE showed duodenitis and proximal jejunitis, and did not show enteritis in any other area. Congested, erythematous and partially depleted mucosa was found in all three patients, and a small area of bleeding was seen in patients B and C (Fig. 2). In all three patients, the most inflamed region was the third part of duodenum, and, in terms of dose distribution, this was closest to the center of irradiation (Figs. (Figs.1,1, ,2).2). These findings were not seen by capsule endoscopy (CE) before CRT. There was no significant stenosis, and capsule retention did not occur. The Lewis scores after CRT in patients A, B and C were 641, 4396 and 782 respectively, and the scores were higher than before CRT in all three cases (Table 2). The percentage volumes of the duodenum receiving ≥45 Gy (V45) in patients A, B and C were 23, 30 and 36%, respectively (Table 3). During treatment, we observed anorexia (grades 1 or 2 according to CTCAE) in all three patients.
This is believed to be the first reported prospective case series of acute RE investigated by CE before and after CRT for ULAPC. Acute RE has been reported in 20-75% of patients as a complication of RT for abdominal or pelvic malignancies [2,3]. However, it was mainly acute radiation ileitis, and there are few reports of duodenitis and jejunitis caused by CRT for ULAPC. In the present study, the patients were checked for any duodenal or small intestinal abnormality by CE before undergoing CRT to enable evaluation of any injury caused by RT. CE showed that injury extended more deeply in the proximal jejunum than the duodenum in all three cases. These jejunal injuries cannot be seen by esophagogastroduodenoscopy, and CE is useful and safe for acute-phase evaluation of patients with CRT for ULAPC.
The third part of the duodenum was more inflamed than the other parts of duodenum and proximal jejunum, and this might be significantly related to the dose distribution of radiation. In relation to the dose distribution and percent V45, the third part of the duodenum was exposed to the highest level of radiation in the duodenum and proximal jejunum, and it was the closest region to the pancreatic head. The dose distribution might be possible to predict the degree of duodenal and jejunal mucosal injuries. However, despite the fact that the V45 value was not the highest, patient B showed the most severe mucosal damage and higher Lewis score than patients A and C. This may have been because the body mass index of patient B was low and there was little fat tissue around the pancreas, and because the third part of the duodenum was closer to the center of irradiation than in patient C.
The entire circumference of the proximal jejunum was included within the radiation field, because tumors of the pancreatic head move less in the craniocaudal direction than the anterior-to-posterior or left-to-right direction. Therefore, the safety margin of the radiation field was greater in the craniocaudal direction.
Reducing the symptoms of acute RE requires paying attention to the radiation dose and irradiation field in the small intestine, and the use of concurrent chemotherapy. Intraoperative RT, which has been used alone or in conjunction with external beam RT, can also help reduce RE , because it is aimed directly at the tumor during surgery, thus avoiding surrounding normal tissues.
The most serious complication of CE is capsule retention, caused by strictures of the intestinal lumen. Usually, strictures due to RE occur 8-12 months after RT, and Kim et al reported that CE may be able to diagnose acute RE safely . In our study, CE findings did not reveal any strictures and CE reached the cecum in all three cases without delay, thus, CE may be useful in diagnosing acute RE. Double balloon enteroscopy can also evaluate radiation jejunitis effectively and safely . However, insertion of the enteroscope is difficult because of the edematous effect of RT, and there is the potential for exacerbating radiation-induced duodenitis and proximal jejunitis. Although computed tomography enterography, magnetic resonance enterography and the biomarkers such as calprotectin or lactoferrin are non-invasive diagnostic tools to evaluate RE, the data on these remain inconclusive .
In conclusion, this case series shows that CE can safely diagnose acute duodenitis and proximal jejunitis caused by CRT for ULAPC, and the dose distribution is possible to predict the degree of duodenal and jejunal mucosal injuries.
The authors thank all endoscopists who participated in the study and Ms. Mina Yamashina for her hearty encouragement and unconditional support.
Osaka Medical Center for Cancer and Cardiovascular Disease; Osaka Red Cross Hospital, Osaka, Japan
Conflict of Interest: Dr. Yamashina received five capsule endoscopies from Company Covidien (Dublin, Ireland). The other authors declare that they have no conflicts of interest