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British Journal of Radiology (2006) 79, 419-424
© 2006 British Institute of Radiology
doi: 10.1259/bjr/51376226
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Characteristics and predictive factors of early-onset diarrhoea during pelvic irradiation

E Y Huang, MD1,2, C J Wang, MD1, H C Hsu, MD1 and L M Sun, MD, MS1

1 Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital, 123 Ta-Pei Road, Niao-Sung Hsiang, Kaohsiung Hsien, Taiwan , 2 School of Traditional Chinese Medicine, Chang Gung University, Taiwan


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
This study reported characteristics and predictive factors of early-onset diarrhoea in patients receiving pelvic irradiation. We retrospectively reviewed 229 patients undergoing radiotherapy alone for cervical or uterine cancer. Oral barium was taken 90 min before simulation. According to contrast medium within small intestine only or colon in simulation films, we categorised patients as normal and rapid transit groups. Small or large volume of small-bowel was also evaluated according to barium distribution of simulation films. Whole-pelvic irradiation (39.6–45 Gy/22–25 fractions) was delivered to all patients initially. We recorded the onset of diarrhoea during pelvic irradiation. The rates of early-onset diarrhoea (<10 Gy) were compared between these two groups. The incidence of diarrhoea before 10 Gy was 7% and 17% (p = 0.138) in patients with normal and rapid transit, respectively. In multivariate analysis, interaction among rapid transit, prior abdomen operation and large small-bowel volume (p = 0.019) were noted for early-onset diarrhoea. Further subgroup analysis revealed that rapid transit (p = 0.046) was a significant factor in patients with both prior abdominal operation and large small-bowel volume. The incidence of early-onset diarrhoea was as high as 40% in this particular group. Patients experiencing early-onset diarrhoea had a higher incidence of moderate to severe diarrhoea (65%) than those without early-onset diarrhoea (23%) (p<0.001). In multivariate analysis, early-onset diarrhoea was the only factor of moderate to severe diarrhoea (p = 0.001). In conclusion, rapid small-bowel transit may be predisposed to early-onset diarrhoea during pelvic radiotherapy in patients with both prior abdominal operations and large small-bowel volume. Early-onset diarrhoea is considered as a predictive factor of diarrhoea of a higher grade.


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Radiation-induced acute diarrhoea is common during abdominal and pelvic irradiation. It results from a variety of different pathophysiological mechanisms, including malabsorption of bile salts and lactose, imbalances in local bacterial flora and changes in the intestinal patterns of motility [1, 2]. Although villus atrophy [3] of the small bowel is a key factor, the cause of diarrhoea is not only pathological, but also a functional change of the intestine. Changes in gastrointestinal (GI) motility during fractionated irradiation precede the appearance of histopathological lesions in the GI tract, and the symptoms experienced particularly within the first week of radiotherapy are directly related to changes in bowel motility [4].

The onset of diarrhoea during pelvic radiotherapy usually takes place in the second to third week of radiotherapy with conventional fractionation. However, unusually and inexplicably early onset of diarrhoea was noted in a few patients. Morphological change of small bowel can not explain the phenomenon. It is known that laxatives such as castor oil can rapidly induce diarrhoea by changing the small bowel motility [5]. Similarly, we hypothesize that patients with rapid small-bowel transit can be predisposed to early-onset diarrhoea during pelvic radiotherapy. Interestingly, we used multivariate analysis and noted interaction among rapid small-bowel transit, prior abdominal operation and large small-bowel volume within pelvis. The result is that it is worth investigating the mechanism of early-onset diarrhoea in the future.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Patients' characteristics
Between January 1996 and January 2004, patients with histologically proven cervix or uterine malignancies were reviewed. The selection criteria of patients were four-field whole-pelvic irradiation and oral barium contrast taken 90 min before simulation [6]. The exclusion criteria of patients were: (1) receiving antispasmodic drugs, laxatives or chemotherapy before or during the first week of radiotherapy; (2) recent history of gastroenteritis; (3) history of diabetes mellitus; or (4) history of pelvis irradiation. Characteristics of 229 patients and treatment are shown in Table 1Go. Orthogonal films including anterior–posterior (AP) and lateral view were taken during simulation. In the AP view, at source–axis distance (SAD) 100 cm, x-axis size is the width (median: 15.5; range 13–18 cm) and y-axis size is the cephalocaudal distance (median: 17; range 15–21 cm). In the lateral view, at SAD 100 cm, z-axis size is the ventrodorsal distance (median: 13; range 11–18 cm). The upper margin of AP film was located at L4–5. The lateral margin was 1–1.5 cm beyond the widest part of the pelvic brim. For lateral film, the anterior margin was anterior part pubic symphysis. The posterior margin is behind S2–3 at least.


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  		Table 1. Characteristics of patients(n = 229)

 
Before radiotherapy, an interview of each patient was performed for information of pelvic radiotherapy. We had explained the possible toxicities of radiotherapy. We informed each patient that she could ask for medication at the onset of symptoms. After the beginning of radiotherapy, we inspected patients weekly if no progression of symptoms was noted, especially during the first 1–2 weeks of radiotherapy. When symptoms attacked or progressed, immediate medication was prescribed to patients according to the bowel habits and stool consistency recorded in the charts. If patients had no improvement of initial diarrhoea with minor antispasmodic drug such as mebeverine, we could change to major antispasmodic medication such as loperamide and the onset of moderate to severe diarrhoea was recorded in the chart. Whole-pelvic irradiation (39.6–45 Gy) of four-field technique was initially administered with 10 MV or 15 MV photons through supine position. The daily fraction dose was 1.8 Gy, five fractions weekly. We reviewed the onset of diarrhoea in chart record. The severity of diarrhoea could be measured according to common toxicity criteria (CTC) [7]. Grade 1 is an increase of 2–3 stools per day over pre-treatment. Grade 2 is an increase of 4–6 stools per day, or nocturnal stools. Grade 3 is an increase of ≥7 stools per day or incontinence; or need for parenteral support for dehydration. Grade 4 is physiological consequences requiring intensive care; or haemodynamic collapse. It was considered moderate to severe diarrhoea when patients had any of the following conditions: (1) CTC Grade 2 or greater diarrhoea; (2) no improvement of initial diarrhoea with minor antispasmodic drug and change to major antispasmodic medication; (3) watery diarrhoea. The dose of onset of diarrhoea was recorded for actuarial analysis.

Definition of small-bowel movement and volume distribution
When barium filled the small intestine only, we defined this as normal bowel transit. If barium could be noted within the colon, rapid bowel transit was categorised. In order to evaluate small-bowel volume/distribution within the whole pelvis target, we used a simple volumetric method. We scored barium-filled amount of small bowel within the radiation fields in orthogonal films. If caudal small-bowel was below inferior aspect of sacroiliac (SI) joint and dorsal small-bowel was behind vertical line of sacral promontory, large-volume distribution was defined. Otherwise, the distribution was classified as small volume. Small or large volume presents corresponding upper/anterior or lower/posterior position of small bowel within pelvis. The early-onset of diarrhoea was defined as diarrhoea before 10 Gy.

Statistics
Univariate analysis of early-onset and moderate to severe diarrhoea rate was performed using Chi-square/Fisher's exact test. For multivariate analysis of early-onset and moderate to severe diarrhoea, we used a logistic regression model with stepwise forward procedure. Age, rapid transit, small-bowel volume, and prior abdominal surgery were evaluated as categorical data. A p-value of less than 0.05 was considered to be statistically significant. The risk of diarrhoea or large-volume distribution was presented as odds ratio (OR) with 95% confidence interval (CI). Data processing and statistics were carried out on a personal computer using the software SPSS 12.0 for Windows (SPSS Inc., Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Early-onset diarrhoea between normal and rapid small bowel transit groups
There were 17 patients (7.4%) with diarrhoea before 10 Gy. No moderate to severe diarrhoea was noted before 10 Gy. The result of univariate analysis is shown in Table 2Go. The incidence of early-onset diarrhoea was 7% and 17% in patients with normal and rapid small bowel transit (p = 0.138), respectively. The corresponding rates were 4% and 40% (p = 0.068) in patients with both large volume and prior abdominal operation.


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  		Table 2. Univariate analysis of factors associated with early-onset and moderate to severe diarrhoea during pelvic irradiation

 
Multivariate analysis of early-onset diarrhoea among patients during pelvic irradiation
We considered the possible predisposed factors for the analysis of early-onset diarrhoea. The results are shown in Table 3Go. If we did not consider interaction, no significant factors were noted. Interestingly, we noted interaction among operation, large volume and rapid transit (OR: 9.29, 95% CI: 1.44–59.93) (p = 0.019). Subgroup analysis revealed that rapid small-bowel transit was a significant factor of early-onset diarrhoea in patients with simultaneous large volume and prior abdominal operation (OR: 15.33, 95% CI: 1.05–224.78) (p = 0.046), but not another combinations.


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  		Table 3. Multivariate analysis of factors associated with early-onset and moderate to severe diarrhoea during pelvic irradiation

 
Early-onset diarrhoea predicts moderate to severe diarrhoea among patients during pelvic irradiation
Incidence of moderate to severe diarrhoea was 65%, and 23% in patients with and without early-onset diarrhoea (p<0.001), respectively. In multivariate analysis, early-onset diarrhoea was the only factor of moderate to severe diarrhoea (p = 0.001) (OR: 6.26, 95% CI: 2.20–17.82) while age, small-bowel volume, prior abdominal operation, and small-bowel transit were adjusted.


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
One of the most serious complications of abdominal or pelvic radiotherapy is bowel damage, leading to nausea, vomiting, diarrhoea and abdominal cramps during or shortly after therapy. These symptoms are probably due to a rapid modification of the intestinal motility and to the structural alteration of the intestinal mucosa (cell loss and altered crypt integrity) [2]. Clinically, fractionated radiotherapy of the pelvis usually results in diarrhoea while dose is around 10–20 Gy. The mechanism is villus atrophy [3] caused by impaired crypt proliferation. According to our results, the incidence of early-onset diarrhoea was about 7%. It is difficult to explain diarrhoea before 10 Gy with the model of cell loss and altered crypt integrity because structural alteration of the intestinal mucosa may not appear before 10 Gy. Hence, small-bowel hypermotility may be considered for the mechanism of early-onset diarrhoea.

The radiation-induced change of small-bowel motility had been reported in some investigations. Yeoh et al conducted a series of human and animal studies about small-bowel motility during or after pelvis/abdomen irradiation. During radiotherapy, increased stool frequency (p<0.001) was associated with more rapid small-intestinal (p<0.01) and whole-gut (p<0.05) transit [8]. 1–6 years after radiotherapy, small intestinal transit (p<0.05) was inversely related to stool frequency [9]. In an animal study, there was an initial increase in frequency followed by a non-significant reduction, but not in the amplitude of ileal pressure waves following fractionated abdominal irradiation (22.5 Gy in 9 fractions at 3 fractions/week). There was no relationship between motility and histology [10]. Erickson et al used an animal model with the same fractionation that dramatically increased the frequency of giant migrating contractions (GMCS) of the small intestine, with the incidence peaking after the second dose. The increased frequency of GMCS associated with abdominal cramps and diarrhoea occurred as early as a few hours after the first radiation fraction, and returned to normal within days of cessation of radiation. Altogether, hypermotility of small bowel is associated with diarrhoea during fractionated irradiation.

Our multivariate analysis revealed interaction among rapid transit, prior abdominal operation and large small-bowel volume in pelvis. Subgroup analysis showed that rapid transit was a significant factor of early-onset diarrhoea in patients with both prior abdominal operation and large volume. Prior abdominal operation [11–13] and small-bowel volume [11–15] are associated with radiation-induced enteropathy. Our previous study noted volume effect of small bowel for acute diarrhoea in patients with prior abdominal operation [16]. When patients have both factors, the possibility of large full-dose volume is high. If small-bowel transit is rapid before radiotherapy, there may be hypermotility within a large volume of the small bowel irradiated. While water can not be absorbed in this segment of small bowel, early-onset diarrhoea may appear. Jankovic et al noted that X-radiation produced acute sensitization (2 h) of rat GI tract to acetylcholine and histamine [17]. Hence, radiation-induced hypermotility effect of neurotransmitters may be enhanced in patients with rapid transit.

The effect of abdominal operation in small bowel distribution is important and associated with enterotoxicity. If small bowel is located in posterior pelvis (i.e. large-volume distribution), patients with prior abdominal operation may have a fixed loop of small bowel that could be repeatedly exposed by fractionated radiotherapy. Gallagher et al [11] reported that pelvic small-bowel volume was larger after pelvic surgery, especially abdominoperineal resection. In post-operative patients with rectosigmoidal and endometrial cancers, 26–65% of fixed small bowel was noted in the posterior pelvis [14, 18, 19]. Operation could exacerbate radiation-induced acute diarrhoea in rectal cancer because small bowel could be fixed in posterior pelvis by operation [12, 20]. We could calculate comparable large-volume distribution (35%) in our study. Limited movement of small bowel within posterior pelvis caused by operation may result in repeated large-volume and full-dose exposure of small bowel. If these patients have rapid small-bowel transit before radiotherapy, hypermotility of large volume can result in early-onset diarrhoea.

Some methods of measurement for transit time of small intestine were reported. Radioisotopes allow accurate quantitation of the pattern and effectiveness of the transit of chyme through the small and large intestines [21, 22]. Birkebaek et al measured healthy adult test subjects using a scintigraphic method with 111In marked single unit tablets. The small intestine transit time was 5 h (median) with an interquartile range of 4–7 h [23]. Benmair et al used a magnetic method for the measurement of small intestinal transit time in a group of 20 normal subjects [24]. The mean transit time was 157.5±63.9 min. Pia de la Maza et al used hydrogen breath test [25] and noted mean intestinal orocecal transit time decreased from 1.7±0.9 h to 1.36±0.9 h after 5 weeks of radiation (p<0.05) [26]. The variations may depend on the methodology. Simulation at 1.5 h after barium intake seems to be applicable for mimicking transit time in our study. Although oral contrast is not the optimal method for transit time of small bowel, we could still note increased incidence of early-onset diarrhoea in patients with short transit time.

The severity of early-onset diarrhoea was mild in our results. The role of early-onset diarrhoea in moderate to severe diarrhoea was tested in our study. We noted that early-onset of diarrhoea was predisposed to moderate to severe diarrhoea in both univariate and multivariate analysis. Patients experiencing early-onset of diarrhoea may be radiosensitive. Hence, more accumulative damage and more severe diarrhoea developed in those who received further fractionated radiotherapy after early-onset diarrhoea. The result suggests that more severe diarrhoea may appear if early onset diarrhoea is noted.

There are some flaws in the present study. The small-bowel volume and transit were evaluated by orthogonal simulation films. Although they are not standard methods, they are acceptable for prediction. Because diabetes mellitus [27–31] and chemotherapy [12, 32] could influence diarrhoea, we excluded patients with these factors and sample size was decreased. Furthermore, the incidences of rapid transit and early-onset diarrhoea were low. Hence, a large sample size is needed to present statistical differences. Regardless, the role of small-bowel transit was established while interaction was considered for multivariate analysis. This is the first clinical result investigated about the association between small-bowel transit and early-onset diarrhoea. Prospective study with more sensitive evaluation for small-bowel volume and transit is encouraged.

Although we focused on acute diarrhoea during whole pelvis irradiation, late bowel complications were also important because quality of life was impaired [33, 34]. Andreyev et al stated that most studies have used inadequate assessments of GI toxicity [35]. The population of our patients included those receiving operations or not. Hence, the radiation dose, field size, and boost technique varied after 39.6–45 Gy whole pelvis irradiations. These factors limited effective assessment of influence of early-onset diarrhoea in late bowel complications. However, the prospective study using more comprehensive records of symptoms, such as diary and questionnaire, is encouraged. Furthermore, our previous study used early-onset diarrhoea as part of severity of diarrhoea and showed correlation between acute and late toxicity [36]. If early-onset diarrhoea appears, the patient may have more severe diarrhoea during subsequent irradiation and increased incidence of late bowel complications. More supportive care and dose/target volume modification to avoid late complications may be considered. In conclusion, early-onset diarrhoea may be associated with rapid small-bowel transit in patients with simultaneous prior abdominal operation and large volume of small-bowel irradiated. Patients with early-onset diarrhoea are predisposed to more severe diarrhoea during subsequent pelvic radiotherapy.

Received for publication May 4, 2005. Revision received August 8, 2005. Accepted for publication August 17, 2005.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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