Sigmoid colon perforation after postoperative hypofractionated intensity‐modulated radiation therapy in a cervical cancer patient

Abstract

Background

Radiation‐induced complication occurs in two phases: acute and chronic toxicities. Bowel perforation is regarded as a chronic toxicity associated with injury to vascular and connective tissue. It is usually noted a few months to several years after radiation treatment (RT).

Case

Herein, we present a case of sigmoid colon perforation relatively early after completion of RT. A 70‐year‐old woman was treated with laparoscopic radical hysterectomy and postoperative hypofractionated intensity‐modulated RT for clinical stage IB1 cervical cancer. RT was delivered with a total dose 4000 cGy in 16 fractions to whole pelvis once a day. Sigmoid colon perforation was found 40 days after completion of RT without any typical signs of perforated viscera. Emergency exploratory laparotomy was performed. Pathology revealed chronic inflammation with mucosal ulceration and submucosal fibrosis, a typical radiation effect.

Conclusion

Although the cause of perforation remains unclear, early‐onset sigmoid colon perforation as an effect of irradiation can occur. We should keep in mind the possibility of perforation in the care of radiated patients who present abdominal pain with atypical presentation regardless of satisfaction of dose constraint for radiotherapy.

1. INTRODUCTION

Radiotherapy to the pelvic area could cause major complications, including small and large bowel (60%‐65%), bladder (20%), and vaginal (10%) complications.1 Radiation injury to the gastrointestinal (GI) tract has two phases: acute and chronic toxicities.2 Acute toxicity is associated with mucosal cell injury which shows acute symptoms such as enterocolitis. It usually occurs within 2 weeks after radiation exposure. On the other hand, chronic toxicity is associated with injury to vascular and connective tissue. It manifests bleeding, obstruction, fistula, and perforation. Chronic toxicity usually shows up a few months to several years after radiation treatment (RT).

Perforation of the colon is one of the least known chronic complications of RT. The University of Texas M. D. Anderson Cancer Center reported that the incidence of colon perforation in a group of patients with stage IB cervical cancer was 0.6% at 20 years.3 The median time from completion of RT to perforation was 13 months (range, 3‐98 months). Although colon perforation is a kind of rare complication, its risk of death is much higher than other GI tract complications without prompt diagnosis and treatment. Risk factors such as reduced body mass index, previous intestinal surgery, inflammatory bowel disease, and pelvic inflammatory disease or diverticulosis have been reported to be associated with radiation enteritis.4 In terms of treatment, radiation dose and faction size, radiation field, radiation technique, and concomitant chemotherapy can be used.5 Reduction in field size, multiple field arrangement, and intensity‐modulated radiation therapy (IMRT) technique are known to be able to reduce complications in pelvic RT.6 For instance, IMRT might provide good target coverage while sparing normal organ such as small and large bowel in gynecological and rectal cancer, with 30% to 40% reduction in acute and chronic GI toxicity.7 Last year, we started to enroll patients to our prospective phase II exploratory trial called as POHIM_RT trial (PostOperative Hypofractionated Intensity‐Modulated Radiation Therapy in cervical cancer). To increase radiobiological effect on tumor and decrease overall treatment time, we adjusted fraction size to 250 cGy with a total dose 4000 cGy in 16 fractions to the whole pelvis. Biological effective dose for early‐reacting tumor was equivalent to a total dose of 4320 cGy in 24 fractions in conventional fractionation. Biological effective dose for late‐reacting tissue (BED3) was 7330 cGy. It was equivalent to a total dose of 4500 cGy in 25 fractions in conventional fractionation. Since it might affect the surrounding normal tissue, IMRT planning was applied for all patients to minimize the incidence of acute and late complications. To the best of our knowledge, there has been no previous report showing severe chronic complication in the setting of early‐onset and adjuvant radiotherapy after surgery for cervical cancer patient. Lin et al have published a brief case‐report of early‐onset sigmoid colon perforation during definitive concurrent chemoradiation treatment in a patient with stage IIB cervical cancer.8 Herein, after approval by the Institutional Review Board, we present a case with sigmoid colon perforation occurring relatively early after completion of RT.

2. CASE

A 70‐year‐old woman (body weight, 40.5 kg; height, 156 cm; BMI, 16.64) visited Samsung Medical Center in September 2017 for regular medical check‐up. A pelvic physical examination revealed visible lesion limited to the cervix and less than 4 cm in the greatest dimension consistent with FIGO (International Federation of Gynecology and Obstetrics) stage IB1 cervical cancer. Pathology results confirmed a diagnosis of invasive squamous cell carcinoma of keratinizing type of the cervix with positive result of human papillomavirus type 33. Tumor marker (squamous cell carcinoma antigen) was elevated up to 3.5 ng/mL. At the same time, there was no specific mucosal lesion in regular check‐up colonoscopy. A subsequent magnetic resonance imaging revealed 2.6‐cm‐sized cervical lesion without evidence of parametrial or vaginal invasion. Positron emission tomography‐computed tomography (PET‐CT) showed focal hypermetabolic lesion in the cervix without evidence of distant metastasis. She denied having a history of abdominopelvic surgery, inflammatory bowel disease, or any pelvic inflammatory disease. She was treated with radical hysterectomy and pelvic lymph node dissection on October 16, 2017. In permanent pathology report, there was no involvement of parametrium, vaginal resection margin, or regional lymph nodes. Tumor size was 2.5 cm in the greatest dimension. There was no lympho‐vascular invasion. However, tumor invasion depth was greater than half of the cervical wall. According to our protocol of POHIMRT trial, she was scheduled to be treated with postoperative radiotherapy alone (4000 cGy in 16 fractions to whole pelvis) from November 21, 2017 to December 15, 2017. During RT, she experienced mild nausea and dyspepsia at 1 week and diarrhea at 2 weeks. Poor oral intake and vague abdominal pain appeared later in the treatment. Overall treatment time was 25 days, including 3 days of interruption. Five days after completion of RT, she visited emergency room due to poor oral intake and chronic lower abdominal pain. While tumor marker was normal, 4‐cm‐sized suspicious lesion at the left vaginal vault was found in abdominopelvic CT, pelvis magnetic resonance imaging, and PET‐CT. Transvaginal ultrasonography‐guided biopsy confirmed chronic inflammation with fibrosis and necrotic tissue without evidence of malignancy. Thus, we scheduled follow‐up in 3 months. However, 1 month later, she visited emergency room again due to aggravating poor oral intake and abdominal pain. In physical examination, tenderness was positive in lower abdomen. There was no fever, tachycardia, rebound tenderness, or guarding in abdomen. Abdominopelvic CT showed large amount of pneumoperitoneum, ascites, and loculated fluid collection with peritoneal wall thickening. Interval improvement was seen in the suspicious lesion of vaginal stump. An emergency exploratory laparotomy was performed which revealed 3‐cm‐sized ulcerative lesion in sigmoid colon. Hartmann operation was completed on 25 January 2018. A pathological exam revealed that there was a full‐thickness ulcer and necrotic exudate on the membrane serosa of the perforation (Figure 1). With a wide range of antibiotics, nutritional support, and intensive care, she was discharged 2 months later in good general condition.

Figure 1.

Histopathologic slide at 20× magnification with hematoxylin and eosin staining showing chronic inflammation with mucosal ulceration and necrotic exudate on the membrane serosa (arrows)

3. DISCUSSION

Chronic complications such as bleeding, obstruction, fistula, and perforation are known as develop several months to years after completion of RT. In previous studies, the median time from completion of RT to perforation was 13 months (range, 3‐98 months).3 In the present case, pain was described as mild. There were no typical peritoneal signs such as rebound tenderness or guarding in physical examination. Thus, it was theoretically difficult to recognize this late effect at an early phase of treatment or during short‐term follow‐up period.

In aspect of risk factors associated with radiation enteritis for this case, she had a history of laparoscopic radical hysterectomy and lower body mass index (<18.5).4 As a treatment factor, only radiation faction size (dose per fraction) was greater than 200 cGy. It was equivalent to total dose 4500 cGy in 25 fractions as conventional fractionation with BED3 for late responding normal tissues. In review of IMRT planning, only small volume of the loop of sigmoid colon was irradiated with maximum dose (Dmax) of 4083 cGy. In general, the result was superior to three‐dimensional conformal RT planning not only for target coverage, but also for sparing normal organ such as small and large bowel. According to Emami and Quantec data representing a tolerance of normal tissue to therapeutic irradiation, the total dose at which 5% of patients were expected to experience enteritis at 5 years (TD5/5) of the colon was about 5500 cGy and the dose at which 50% of patients were expected to experience enteritis at 5 years (TD50/5) was 6500 cGy.9 Although previous surgery created adhesions which prevented loops of the bowel from moving during RT, it was still below than TD5/5 of the colon. Thus, the probability of sigmoid colon perforation as an effect of irradiation might be quite low. Radiation total dose, radiation field, radiation technique, or concomitant chemotherapy was not associated with the present case.

On the other hand, iatrogenic bowel injury during operation could be considered. While large bowel was the more common place of injury than small bowel and rectum, the incidence was between 0.5% and 0.7%. During the era of laparoscopic hysterectomy, the incidence of bowel injury further decreased from 0.14% to 0.09%.10 In our case, although she complained mild lower abdominal pain consistently after operation, there was no evidence of perforation at postoperative CT image which was performed to rule out ileus. After that, she complained similar degree of pain steadily during RT. At the time of perforation, surgeon found localized 3‐cm‐sized hole in sigmoid colon. The result of pathology revealed chronic inflammation with mucosal ulceration and sub‐mucosal fibrosis limited to focal perforated area, a typical radiation effect. In acute radiation injury, pathologic change is associated with inflammatory cell infiltrate, reduced crypt mitoses, epithelial denudation, and ulceration. On the other hand, obliterate endarteritis, sub‐mucosal fibrosis, lymphatic dilatation, and tissue ischemia and necrosis are related to chronic radiation injury. In this case, both acute and chronic radiation changes had developed at the same time. While most of radiation changes would occur diffusely, this case showed radiation change only limited to focal perforated area.

4. CONCLUSION

In summary, although the cause of perforation remains unclear, early‐onset sigmoid colon perforation as an effect of irradiation can occur. Therefore, clinicians should keep in mind the possibility of perforation in the care of radiated patients who present abdominal pain with atypical presentation regardless of satisfaction of the dose constraint for radiotherapy.

CONFLICT OF INTEREST

None declared.

AUTHORS' CONTRIBUTION

All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Conceptualization, W.P., J.W.L.; Methodology, W.P.; Investigation, Y.L.C., H.K.K.; Formal Analysis, H.K.K.; Resources, J.W.L., Y.L.C.; Writing ‐ Original Draft, H.K.K.; Writing ‐ Review & Editing, W.P.; Visualization, Y.L.C.; Supervision W.P.

Kim H, Park W, Choi Y‐L, Lee J‐W. Sigmoid colon perforation after postoperative hypofractionated intensity‐modulated radiation therapy in a cervical cancer patient. Cancer Reports. 2018;1:e1129. 10.1002/cnr2.1129