Is the irradiated small bowel volume still a predictor for acute lower gastrointestinal toxicity during preoperative concurrent chemo-radiotherapy for rectal cancer when using intensity-modulated radiation therapy?
© Xu et al. 2015
Received: 14 July 2015
Accepted: 10 December 2015
Published: 18 December 2015
The small bowel (SB) represents the most important dose-limiting structure in pelvic radiotherapy (RT). However, we observed that the majority of rectal cancer patients who received preoperative pelvic intensity modulated RT (IMRT) developed acute tenesmus without watery diarrhea. The objective of this study is to determine if the RT dose to SB affects the acute lower gastrointestinal toxicity (ALGIT) in rectal cancer patients who received neoadjuvant concurrent chemotherapy-IMRT. We will also evaluate if patient and tumor factors affect the ALGIT.
We retrospectively analyzed 63 rectal cancer patients that consecutively received preoperative IMRT (45 Gy for pelvis and 50 Gy for gross tumor in 25 fractions) with concurrent chemotherapy (oxaliplatin 130 mg/m2 on day 1 and capecitabine 825 mg/m2, twice per day from day 1 to day 14, week 1 and 4) between May 2012 and May 2013. The ALGIT was assessed with Common Terminology Criteria for Adverse Events version 3. The patients were stratified into two groups (with and without grade ≥2 ALGIT). The effect of SB volume receiving 5 to 40 Gy (V5 to V40) at a 5 Gy interval dose level on grade ≥2 ALGIT was evaluated. The volume of small bowel is defined as the volume of the small bowel loop. Other factors evaluated include patient’s age and gender, tumor size and location and preexisting number of daily bowel movements.
Overall, grade ≥2 ALGIT occurred in 57 % (36/63) patients. There was no significant difference between the two groups of patients (with and without grade ≥2 ALGIT) in SB V5 to V40, patient’s age and gender, tumor location and preexisting number of daily bowel movements. There was a significant difference between the two groups of patients in tumor volume (with grade ≥2 ALGIT: 115.5 ± 85.5 cm3 versus without grade ≥2 ALGIT: 58.5 ± 25.2 cm3, p = 0.0001). Multivariate analysis revealed no association between the dose SB received (V5 to V40) and the grade ≥2 ALGIT after adjusting for the tumor volume.
With IMRT technique used in rectal cancer patients undergoing preoperative chemo-radiotherapy, the acute lower GI toxicity is not associated with small bowel V5 to V40; instead it is associated with rectal tumor size.
Radiation therapy plays an important role in preoperative and postoperative therapy for locally advanced rectal cancer [1–4]. Radiation-induced lower GI toxicity is the main concern. Serious acute lower GI toxicity was reported in 12 to 44 % of patients undergoing radiotherapy alone or with concurrent chemotherapy in multicenter randomized clinical trials [4, 5]. The small bowel represents the most important dose-limiting structure in the pelvic radiation therapy. Dosimetric studies revealed association between the lower GI toxicity and the irradiated small bowel volume [6, 7].
Since the German trial reported that preoperative chemo-radiotherapy improved local control and was associated with reduced toxicity as compared with postoperative chemo-radiotherapy, preoperative concurrent chemo-radiotherapy has become a standard of care for locally advanced rectal cancer (T3–4 and/or N positive) [4, 8]. A study has shown that the small bowel volume irradiated could be reduced in patients undergoing preoperative radiotherapy as compared with those undergoing postoperative radiotherapy . Intensity-modulated radiation therapy (IMRT) has been confirmed to be advantageous at protection of the organs at risk such as bladder, femoral head and small bowel, and widely accepted as a relatively safe and effective radiotherapy method in the treatment of rectal cancer [10, 11]. Using IMRT technique further decreases the small bowel in the radiation field as compared to those using 3D conformal radiotherapy. Hence, the acute lower GI toxicity could be decreased significantly when IMRT used in preoperative chemo-radiation therapy. In clinical practice, we noticed that most rectal cancer patients who received preoperative IMRT typically presented with tenesmus and a feeling of incomplete defecation without watery diarrhea and abdominal pain. It seems that such side effects were induced rather by rectal reaction to radiation than by small bowel inflammation.
To better understand these clinical presentations, we attempted to find out if the irradiated small bowel volume still is a predictor for acute lower GI toxicity during preoperative concurrent chemo-radiotherapy for locally advanced rectal cancer when IMRT is utilized. We also examined other potential predictors for acute lower GI toxicity in this patient population.
Patients and methods
Acute GI toxicity
N = 63
Grade < 2
N = 27
N = 36
Tumor volume (cc)
Tumor location (cm from the anal verge)
Pre-existing number of daily bowel movements
All patients underwent a contrasted CT simulation with a supine position. Oral contrast was given 30 min prior to simulation in order to differentiate the small bowel from the large bowel. A planning CT scan of the lower abdomen and pelvis was obtained at 5-mm intervals from the inferior edge of the second lumbar vertebrae (L2) through the mid-thigh. The CT data was transferred to the Xio treatment planning system (CMS Xio Version4.6 and Monaco 3.2.0, Elekta CMS Software, Maryland Heights, MO) for delineating the target volume and organs at risk (OARs).
The IMRT plan consisted of 5 coplanar beams with the isocenter set at the center of PTV-GTV, arranged at 55°, 115°, 180°, 245°and 310°. The dose prescribed to PTV-GTV was 50 Gy/25fractions and to PTV-CTV was 45 Gy/25fractions. The doses to OARs were limited as follows: V45 < 35 % for bladder, V30 < 15 % for femoral head, and V30 < 60 % and Dmax <45 Gy for small bowel. All patients were irradiated with one fraction daily for five consecutive days per week. The prescription dose was to cover at least 95 % volume of PTV.
A small bowel dose-volume histogram (DVH) was generated for each patient. The absolute and relative volumes of small bowel receiving doses between 5 Gy and 40 Gy were recorded from the DVH at 5-Gy interval (V5 to V40) according to the study of Baglan KL .
The chemotherapy that patients received during the radiation therapy was per an institutional protocol . All patients had two 3-week cycles of chemotherapy during the course of radiation therapy. The chemotherapy regimen included oxaliplatin (130 mg/m2on day-1) and capecitabine (825 mg/m2, twice per day from day-1 to day-14) every 3 weeks.
Scale for acute GI toxicity based on common toxicity criteria v3.0
Increase of <4 stools per day over pretreatment
Increase of 4–6 stools per day or nocturnal stools
Increase of ≥7 stools per day or incontinence or need for parenteral support for dehydration
Physiologic consequences requiring intensive care of hemodynamic collapse
The chi-squared test was used to compare the proportions of the two patient groups for the baseline patient characteristics and RT delivery parameters. The independent sample T-test was used to compare the treatment target volume, small bowel volume, the volumes of small bowel receiving doses between 5 Gy and 40 Gy between the two groups (patients with grade <2 and ≥ 2 lower GI toxicity). A p value of ≤ .05 was considered significant. Statistical analyses were conducted using the Statistical Analysis Systems software package, version 9.3 (SAS Institute, Cary, NC).
Overall, acute grade ≥ 2 lower GI toxicity during radiotherapy occurred in 57.1 % (36/63) patients. Among them, 14 were grade 2, 22 grade 3 and 0 grade 4. Only 4 of 36 had watery diarrhea at the second, seventh, eleventh and sixteenth fraction of radiotherapy. The remaining 27 patients experienced grade 0 and 1 lower GI toxicities. The median age of the entire group of patients was 55 (range 30–78). Most patients were male (71.4 %) and had a clinical stage of T3-4 (95.2 %) or were N positive (93.7 %). The tumor located 2–12 cm from the anal verge with a median of 6 cm. The tumor volume ranged from 20 cm3 to 318 cm3 with a median volume of 92 cm3 (Table 1). Patients with a larger tumor volume had a significantly higher rate of grade ≥ 2 toxicity (59 ± 25 cm3 vs 116 ± 86 cm3, p = 0.0004). Almost half of the patients (32/63) had pre-existing grade 2 or above frequent bowel movements secondary to rectal tumor (Table 1). It was found that 52.4 % (33/63) patients had either stable symptoms or had various extents of improvement in symptoms during the radiotherapy.
Comparison of small bowel dose-volume in patients with grade < 2 to grade ≥2 acute lower GI toxicity
Small bowel volume(mean ± SD, cm3)
268 ± 173
217 ± 107
230 ± 154
189 ± 99
203 ± 138
169 ± 95
174 ± 124
143 ± 86
127 ± 105
103 ± 68
75 ± 78
60 ± 49
47 ± 63
37 ± 37
30 ± 49
23 ± 24
Factors associated with grade ≥ 2 lower GI toxicity
OR (95 % CL)
OR (95 % CL)
0.376 0.108 1.308
Tumor volume (cc)
0.147 0.043 0.499
0.272 0.080 0.922
Small bowel V5 (cc)
Small bowel V10 (cc)
Small bowel V15 (cc)
Small bowel V20 (cc)
Small bowel V25 (cc)
Small bowel V30 (cc)
Small bowel V35 (cc)
Small bowel V40 (cc)
The most interesting finding of this study is no correlations between the dose-volume parameters of small bowel (V5 to V40) and the acute lower GI toxicity during preoperative concurrent chemo-radiotherapy for rectal cancer when IMRT is used. This study also revealed that the rectal tumor volume is a predictor of grade ≥ 2 lower GI toxicity. To our knowledge, this is the first study to report that with IMRT, the acute lower GI toxicity in this patient population is mainly influenced by rectal tumor volume but not small bowel dose-volume parameters.
Preoperative radiotherapy with IMRT decreased small bowel volume in the pelvic radiation field
Minsky et al. showed a dramatic decrease of small bowel volume in the radiation field for patients that received preoperative radiotherapy when compared with postoperative radiotherapy (212 ± 44 cm3 versus 462 ± 129 cm3, p = 0.002) . Sauer et al. found that ≥ grade 3 diarrhea occurred in patients treated preoperatively significantly less frequent than those treated postoperatively (12 % vs. 18 %, p = 0.04) . To further reduce small bowel volume in the radiation field, IMRT has been used in several studies in the preoperative chemo-radiation therapy for rectal cancer [15, 16]. Two dosimetric studies showed that the small bowel volume was reduced significantly in the radiation field with IMRT [17, 18]. In the study by Arbea L et al., the small bowel V40 with IMRT was only one third of the V40 treated with conventional 3-field technique (68.9 cc vs. 178.3 cc, p < 0.01) . In our study, all patients received preoperative radiotherapy with IMRT technique. The small bowel V40 in the current study was only 23–30 cc which is smaller than the small bowl V40 (68.9 cc) in patients treated with IMRT in the study of Arbea et al. Our study suggests that the small bowel V5-V20 are no longer predictors for grade ≥ 2 lower GI toxicity when an irradiated small bowl volume is reduced to a very low level by using modern radiotherapy technique such as IMRT.
Lower GI toxicity is the consequence of rectal irradiation
It is well known that the symptoms of small bowel and rectal injury are different. The symptoms from acute small bowel injury include watery diarrhea, colicky abdominal pain, bloating, loss of appetite, nausea and dehydration . On the other hand, the symptoms from rectal injury typically include soft or diarrhea-like stools, rectal pain and tenesmus (a sense of rectal distention with cramping and frequency) . Studies have shown that patients treated with chemotherapy alone had a risk of around 20 % in developing ≥ grade 3 treatment-related diarrhea  and adding chemotherapy concurrently to radiotherapy increased the frequency and severity of diarrhea . In theory, diarrhea caused by chemotherapy should occur in the course of chemotherapy and could be cured in a short duration. In our study, most patients presented tenesmus. We believe that the occasional watery diarrhea of 4 patients in our study was caused by concurrent chemotherapy since they only occurred during the week of receiving chemotherapy and was cured in a week.
Primary tumor volume influences the lower GI toxicity
Another finding in this study was that the most common acute lower GI toxicity was tenesmus. The gross tumor volume was the only independent influencing factor for the acute lower GI toxicity. The larger the tumor volume the more frequent bowel movements (115.5 ± 85.5 cm3 versus 58.5 ± 25.2 cm3 for grade ≥ 2 and grade 0–1, p = 0.000). Given that most patients had no watery diarrhea, we believe that the named lower GI acute toxicity is a rectal reaction to the tumor and to the radiation injury. In the study of Myerson RJ et al., although they used the 3D-CRT technique, they also found that proctitis was the most common acute toxicity (5/37) during preoperative chemo-radiotherapy and associated with large tumors (PTV ≥ 500 cc). There was only one patient who had enteritis during the treatment course .
Wireless whole gastrointestinal video capsule endoscopy
Small bowel dose-volume for the two patients who underwent VCE examination
Small bowel volume (cm3)
Quantifying the lower GI toxicity
Although there were many reports concerning the acute and chronic small bowel toxicity in pelvic radiation therapy, little data has been published quantifying the details of the toxicity such as extent, timing, duration, correlation with chemotherapy, etc. It is very hard to evaluate the lower GI toxicity via the status of stools for rectal cancer, because for most patients, the most common symptom at the time of diagnosis is increasing frequency of stools with or without mixed blood. Among the 63 patients in our study, the number of pre-existing daily bowel movements was found to be 1 time in 6 (9.5 %) patients, 2–3 times in 25 (39.7 %) patient, 4–6 times in 25(39.7 %) patients and ≥ 7 stools in 7 patients (11.1 %) (see Table 1). Almost half of these patients presented with grade ≥ 2 bowel toxicity before initiating radiotherapy treatment. Moreover, both RTOG  and CTCAE  toxicity scales for lower GI toxicity are simple and rapidly assessable, but provide limited information. For example, they do not assess the development of anorectal symptoms such as tenesmus which is the most common symptom during the pelvic irradiation, especially for rectal cancer treated with IMRT technique. A modified questionnaire from the Inflammatory Bowel Disease Questionnaire (IBDQ) and Vaizey Incontinence questionnaire may be more sensitive and useful for toxicity data collection during the treatment and follow-up [30, 31]. Such questionnaires include much more information when compared to RTOG and CTCAE scales.
Limitations of this study include its retrospective nature, a lack of information on total small bowel volume and details of toxicity.
When small bowel volume in the radiation field was reduced to a low level with IMRT, it was no longer as an influencing factor for acute lower GI toxicity. The radiation-induced lower GI symptoms such as tenesmus without watery diarrhea during pelvic IMRT may be caused by the rectal tumor itself and rectal reaction to radiotherapy. A future prospective study is warranted to investigate the details of lower GI toxicity during treatment and early follow-up, by using a real-time recorded clinical note, modified questionnaire and whole gastrointestinal wireless capsule endoscopy.
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