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The British Journal of Radiology logoLink to The British Journal of Radiology
. 2015 Oct 16;88(1055):20150054. doi: 10.1259/bjr.20150054

Predictors of late bowel toxicity using three different methods of contouring in patients undergoing post-operative radiation for cervical cancer

Supriya Chopra 1,✉, Rahul Krishnatry 2, Tapas Dora 1, Sadhna Kannan 3, Biji Thomas 1, Supriya Sonawone 1, Reena Engineer 2, Siji Paul 1, Reena Phurailatpam 1, Umesh Mahantshetty 2, Shyam Shrivastava 2
PMCID: PMC4743445  PMID: 26394195

Abstract

Objective:

This study investigates the correlation between dose–volume histogram derived from three bowel contouring methods and late toxicity in patients undergoing post-operative radiation therapy (PORT) for cervical cancer.

Methods:

From June 2010 to May 2013, 103 patients undergoing PORT were included. Three different contouring methods were used: (a) individual small bowel (SB) and large bowel (LB) loops, (b) total bowel (TB; including SB and LB) and (c) peritoneal cavity (PC). The volume of SB, LB, TB and PC receiving 15, 30 and 40 Gy was calculated. Acute and late bowel toxicities were scored using Common Terminology Criteria for Adverse events v. 3.0. Receiver operating characteristic curve identified thresholds predicting late toxicity with the highest specificity. All data were dichotomized across these thresholds. Univariate and multivariate analyses were performed using SPSS® v. 20 (IBM Corporation, Armonk, NY; formerly SPSS Inc., Chicago, IL).

Results:

On univariate analysis, V30 PC ≥ 900 cm3 (p = 0.01), V40 PC ≥ 750 cm3 (p = 0.03) and V40 TB ≥ 280 cm3 (p = 0.03) and use of concurrent chemotherapy (p = 0.03) predicted grade ≥II acute toxicity. On multivariate analysis, use of concurrent chemotherapy [odds ratio (OR) 3.5, 95% confidence interval (CI) 1.1–11.1, p = 0.03] and V30 PC ≥ 900 cm3 (OR 2.3, 95% CI 1–5.5, p = 0.05) predicted acute grade ≥II toxicity. On univariate analysis for late toxicity, SB (V30 ≥ 190 cm3, p = 0.009; V40 ≥ 150 cm3, p = 0.03), LB (V15 ≥ 250 cm3, p = 0.04), V40 PC (V40 ≥ 750 cm3, p = 0.001) and presence of acute grade ≥III toxicity (p = 0.006), treatment technique (three-dimensional conformal radiation or intensity modulated radiotherapy, p = 0.02) predicted more than or equal to grade ll late bowel toxicity. On multivariate analysis, only body mass index ≥25 kg m−2 (OR 7.3, 95% CI 1.6–31.6, p = 0.008) and presence of acute grade III toxicity predicted toxicity (OR 5.1, 95% CI 1.4–18.1, p = 0.007).

Conclusion:

V30 PC ≥ 900 cm3 and use of concurrent chemotherapy independently predicts acute toxicity. Presence of acute grade ≥III toxicity independently predicts late toxicity. Minimizing dose to PC subvolumes can therefore reduce both acute and late toxicities.

Advances in knowledge:

Study establishes PC thresholds that can minimize both acute and late bowel toxicities.

INTRODUCTION

Adjuvant radiation is considered the standard of care in patients with cervical cancer with post-operative risk factors,1 however, predisposes patients to bowel toxicity.2 While various studies3–6 have evolved recommendations to limit acute toxicity, it is essentially based on patients with rectal cancer. Extrapolation of these data to patients with cervical cancer though intuitive is limited owing to the differences in the post-operative anatomy, chemotherapy and use of brachytherapy. Furthermore, the contouring methods and recommendations to limit bowel dose are also not uniform. The recent organ at risk contouring guidelines by the Radiation Therapy Oncololgy Group (RTOG)7 suggests delineation of large bowel (LB) and small bowel (SB) separately for gastrointestinal (GI) tumours while peritoneal cavity (PC) for gynaecological malignancies. We recently reported strong correlation between dose–volume histogram (DVH) of SB and LB and grade ≥III late bowel toxicity in patients receiving adjuvant radiation for cervical cancer.8 As the RTOG recommends contouring PC,7 we compared three methods of bowel contouring for the prediction of late toxicity.

METHODS AND MATERIALS

From January 2010 to May 2013, patients undergoing adjuvant or salvage pelvic chemoradiation within context of ongoing institutional trials were included.

Simulation and treatment planning

The details of patient simulation, target delineation and planning have been previously described.8 All patients received 50 Gy/25 fractions/5 weeks with concomitant weekly cisplatin (40 mg m−2). This was followed by vaginal brachytherapy. For the purpose of this study, planning CT scans were retrieved and total bowel (TB) was contoured as outer wall for both SB and LB (individual loops beyond sigmoid up to 2 cm above planning target volume) and PC as per RTOG guidelines (Figure 1). No editing of clinical target volume or planning target volume was performed in the regions of overlap. The absolute volumes receiving 15 Gy (V15), 30 Gy (V30) and 40 Gy (V40) were derived.

Figure 1.

Figure 1.

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CT showing contours of small bowel (SB; white arrows), large bowel (LB; dotted arrows), total bowel (SB + LB) and peritoneal cavity (black arrow).

Toxicity recording

All patients completed the Common Terminology Criteria for Adverse Events at baseline, during treatment and subsequently at follow-up. The highest grade of GI toxicity within 3 months of treatment was recorded as acute toxicity. Thereafter, the worst score during follow-up was recorded as late toxicity. Proctitis was not considered as a bowel event.

Statistical analyses

Statistical analyses were performed using Statistical Package for Social Sciences (SPSS®, v. 20.0.1; IBM Corporation, Armonk, NY; formerly SPSS Inc., Chicago, IL). The grade of acute and late bowel toxicities was categorized as grade ≤II and grade ≥III. Receiver operating characteristic (ROC) curve was used to identify the thresholds of SB, LB, TB and PC that predict late grade ≥II toxicity with the highest specificity and were used to dichotomize data for statistical analysis. Predictive probability of grade ≥II late bowel toxicity was derived using actual event data. Using a cut-off value of 5% late toxicity, bowel dose–volume thresholds were determined and predictive probability plots were generated such that restricting dose below the proposed area under the curve would minimize incidence of late toxicity to <5%. Univariate analysis for predictors of acute and late bowel toxicities was performed using Fisher's exact test. Patient- and treatment-related factors with p-value <0.05 were included in multivariate analysis using binary logistic regression with backward conditional method. Parameters with odds ratio (OR) of >1 and p ≤ 0.05 were considered as significant predictors of toxicity.

RESULTS

Baseline characteristics

A total of 103 patients with median age of 48 years (35–65 years) were included. While 72 patients received upfront adjuvant radiation, 31 patients received radiation for post-operative central or parametrial recurrence. The median body mass index was 24.6 kg m−2 (15.8–37.7 kg m−2). Only 5 (4.8%) patients had history of abdominal surgeries, and 12 (11.7%) patients had pre-existing diabetes or hypertension. The surgical procedure was hysterectomy with or without salpingo-oophrectomy in 64 (72.1%) patients and Wertheim's hysterectomy in 39 (37.9%) patients. Intensity-modulated radiotherapy (IMRT) was used in 60 (58.2%) patients and three-dimensional conformal radiation (3D CRT) in 43 (41.8%) patients; 87 of 103 (84.5%) patients received weekly cisplatin.

Toxicity

Acute grade I, II, III bowel toxicity was observed in 38 (36.9%), 42 (40.8%) and 21 (20.4%) of patients, respectively, acute toxicity grade was not known for two patients. No grade IV toxicity was observed. Overall, 2 of 21 patients developed severe emesis within the first week of chemoradiation necessitating hospitalization. This was attributed to concurrent chemotherapy. Other common acute toxicities were diarrhoea and abdominal cramps and were managed with oral medications without any treatment breaks or radiation dose modifications.

At the median follow-up of 26 months (2–46 months), the grade I, II, III, IV and V late bowel toxicity was observed in 37 (35.9%), 47 (45.6%), 12 (11.7%), 5 (4.8%) and 2 (1.9%) patients, respectively. The most common late grade II toxicity was lower abdominal pain followed by anorexia, haemorrhage, diarrhoea and distention of the abdomen. The late grade III toxicity included diarrhoea (n = 3) and obstruction (n = 2); grade V toxicity was seen in two patients with SB perforation leading to death after 5 and 9 months of chemoradiation. Both patients had no pre-existing risk factors, and however, were treated with 3D CRT with LB doses more than the previously recommended threshold (V15 SB, 68 and 167 cm3, and V15 LB, 309 and 337 cm3, respectively). One patient underwent emergency exploration following acute abdomen however succumbed to intestinal perforation within 24 h of surgery. Another patient refused medical intervention following diagnosis of subacute obstruction and died within 2 weeks of presenting with subacute bowel obstruction.

Dose–volume histogram parameters and toxicity

On ROC analysis, the dose cut-off values with the highest specificity for V15, V30 and V40 of SB, LB, TB and PC for the prediction of late toxicity were 275, 190 and 150 cm3 (SB); 250, 100 and 90 cm3 (LB); 450, 330 and 280 cm3 (TB) and 1200, 900 and 750 cm3 (PC), respectively.

Acute toxicity

Univariate and multivariate analyses

Univariate analysis for acute grade ≥II and ≥III toxicity is depicted in Table 1. On multivariate analysis, use of concurrent chemotherapy [OR 3.5, 95% confidence interval (CI) 1.1–11.1, p = 0.03] and V30 PC ≥ 900 cm3 (OR 2.3, 95% CI 1–5.5, p = 0.05) predicted acute grade ≥ II toxicity. On restricting the statistical analysis to patients receiving concurrent chemoradiation, none of the parameters predicted acute toxicity (Table 2).

Table 1.

Univariate analysis of treatment-related parameters predicting acute bowel toxicity

Variables Strata (n) Grade ≥II, absent Grade ≥II, present p-value Grade ≥III, absent Grade ≥III, present p-value
Age (years) <48 20 31 0.93 38 13 0.12
≥48 20 32 45 7
Type of hysterectomy Wertheim's 15 24 0.95 32 7 0.76
Simple 35 45 66 14
Type of RT IMRT 25 34 0.52 51 8 0.03
3D CRT 14 25 27 12
Concurrent chemotherapy No 10 6 0.03 15 1 0.14
Yes 30 57 68 19
Body mass index (kg m−2) <25 25 31 0.18 47 9 0.34
≥25 15 32 36 11
Abdominal surgery Single 22 50 0.33 54 18 0.30
Multiple 3 2 5 0
Co-morbidities Yes 7 5 0.14 9 3 0.60
No 33 58 74 17
Tobacco use Yes 8 7 0.21 13 2 0.51
No 32 56 70 18
V15 SB (cm3) ≥275 7 14 0.56 16 5 0.56
<275 33 49 67 15
V30 SB (cm3) ≥190 7 18 0.20 19 6 0.50
<190 33 45 64 14
V40 SB (cm3) ≥150 7 17 0.26 18 6 0.43
<150 33 46 65 14
V15 LB (cm3) ≥250 2 11 0.06 9 4 0.26
<250 38 52 74 16
V30 LB (cm3) ≥100 9 25 0.07 27 7 0.83
<100 31 38 56 13
V40 LB (cm3) ≥90 7 21 0.07 21 7 0.38
<90 33 42 62 13
V15 TB (cm3) ≥450 7 18 0.20 20 5 0.93
<450 33 45 63 15
V30 TB (cm3) ≥330 4 15 0.07 16 3 0.65
<330 36 48 67 17
V40 TB (cm3) ≥280 3 15 0.03 13 5 0.32
<280 37 48 70 15
V15 PC (cm3) ≥1200 14 28 0.34 35 7 0.55
<1200 26 35 48 13
V30 PC (cm3) ≥900 6 24 0.01 22 8 0.23
<900 34 39 61 12
V40 PC (cm3) ≥750 4 17 0.03 15 6 0.23
<750 36 46 68 14
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3D CRT, three-dimensional conformal radiation; IMRT, intensity-modulated radiotherapy; LB, large bowel; PC, peritoneal cavity; RT, radiotherapy, SB, small bowel; TB, total bowel; V15–V40, volume of bowel getting the specified dose in gray.

Table 2.

Univariate analysis for acute bowel toxicity in patients receiving concurrent chemoradiation (n = 87)

Variables Strata (n) Grade ≥II, absent Grade ≥II, present p-value Grade ≥III, absent Grade ≥III, present p-value
Age (years) <48 15 30 0.81 32 13 0.09
≥48 15 27 36 6
Type of hysterectomy Wertheim's 9 21 0.52 23 7 0.80
Simple 21 36 45 12
Type of RT IMRT 18 31 0.75 41 8 0.07
3D CRT 11 22 22 11
Concurrent chemotherapy No 12 4 0.46 15 1 0.92
Yes 72 15 81 6
Body mass index (kg m−2) <25 19 29 0.26 40 8 0.19
≥25 11 28 28 11
Abdominal surgery Single 17 45 0.08 45 17 0.32
Multiple 3 2 5 0
Co-morbidities Yes 3 4 0.62 4 3 0.16
No 27 53 64 16
Tobacco use Yes 6 6 0.22 10 2 0.64
No 24 51 58 17
V15 SB (cm3) ≥275 5 12 0.62 12 5 0.40
<275 25 45 56 14
V30 SB (cm3) ≥190 6 14 0.63 15 5 0.69
<190 24 43 53 14
V40 SB (cm3) ≥150 6 14 0.63 15 5 0.69
<150 24 43 53 14
V15 LB (cm3) ≥250 2 10 0.16 9 3 0.77
<250 28 47 59 16
V30 LB (cm3) ≥100 8 22 0.26 24 6 0.76
<100 22 35 44 13
V40 LB (cm3) ≥90 6 18 0.25 18 6 0.66
<90 24 39 50 13
V15 TB (cm3) ≥450 5 15 0.30 16 4 0.82
<450 25 42 52 15
V30 TB (cm3) ≥330 3 12 0.19 13 2 0.38
<330 27 45 55 17
V40 TB (cm3) ≥280 3 12 0.19 11 4 0.61
<280 27 45 57 15
V15 PC (cm3) ≥1200 9 25 0.20 27 7 0.82
<1200 21 32 41 12
V30 PC (cm3) ≥900 5 20 0.07 18 7 0.37
<900 25 37 50 12
V40 PC (cm3) ≥750 4 15 0.16 14 5 0.59
<750 26 42 54 14
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3D CRT, three-dimensional conformal radiation; IMRT, intensity-modulated radiotherapy; LB, large bowel; PC, peritoneal cavity; RT, radiotherapy; SB, small bowel; TB, total bowel; V15–V40, volume of bowel getting the specified dose in gray.

Late toxicity

On univariate analysis, SB (V30 ≥ 190 cm3, p = 0.009; V40 ≥ 150 cm3, p = 0.03), LB (V15 ≥ 250 cm3, p = 0.04), V40 PC (V40 ≥ 750 cm3, p = 0.001) and presence of acute more than or equal to grade II late bowel toxicity (p = 0.006), treatment technique (3D CRT or IMRT, p = 0.02) predicted late grade ≥bowel toxicity. In addition, presence of acute grade II/III toxicity (p = 0.02 and p = 0.0001), V40 TB ≥ 280 cm3 (p = 0.004) and V30 PC ≥ 900 cm3 (p = 0.01), treatment technique (3D CRT or IMRT, p = 0.0002) predicted grade late toxicity (Table 3). On multivariate analysis, only body mass index ≥25 kg m−2 (OR 7.3, 95% CI 1.6–31.6, p < 0.008) and presence of acute grade ≥III toxicity predicted late grade ≥II toxicity (OR 5.1, 95% CI 1.4–18.1, p = 0.007). Using actual event data and binary logistic regression, predictive probability plots for various dose–volume thresholds were generated. Restricting bowel doses below the proposed thresholds could restrict late toxicity ≤5% (Figure 2).

Table 3.

Univariate analysis of treatment-related parameters predicting late bowel toxicity

Variables Strata (n) Grade ≥II, absent Grade ≥II, present p-value Grade ≥III, absent Grade ≥III, present p-value
Age (years) <48 36 9 0.45 42 3 1.0
≥48 36 6 39 3
Type of hysterectomy Wertheim's 33 6 0.60 60 4 1.0
Simple 51 13 36 3
Type of RT IMRT 44 5 0.02 49 0 0.002
3D CRT 23 10 27 6
Concurrent chemotherapy Yes 72 15 0.48 81 6 1.0
No 12 4 15 1
Body mass index (kg m−2) <25 37 11 0.07 45 3 1.0
≥25 35 4 36 3
Abdominal surgery Single 59 13 0.25 66 6 0.72
Multiple 3 2 5 0
Co-morbidities Yes 9 3 0.69 10 2 0.18
No 75 16 86 5
Tobacco use Yes 14 1 0.29 14 1 0.98
No 70 18 82 6
Acute grade II Yes 48 15 0.11 56 7 0.04
No 36 4 40 0
Acute grade III Yes 12 8 0.01 14 6 0.0001
No 72 11 82 1
V15 SB (cm3) ≥275 15 6 0.21 18 3 0.14
<275 69 13 78 4
V30 SB (cm3) ≥190 16 9 0.01 21 4 0.05
<190 68 10 75 3
V40 SB (cm3) ≥150 16 8 0.06 19 5 0.07
<150 68 11 77 2
V15 LB (cm3) ≥250 8 5 0.06 9 4 0.005
<250 76 14 87 3
V30 LB (cm3) ≥100 25 9 0.17 30 4 0.21
<100 59 10 66 3
V40 LB (cm3) ≥90 20 8 0.15 24 4 0.08
<90 64 11 72 3
V15 TB (cm3) ≥450 18 7 0.23 22 3 0.35
<450 66 12 74 4
V30 TB (cm3) ≥330 13 6 0.11 16 3 0.11
<330 71 13 80 4
V40 TB (cm3) ≥280 12 6 0.09 14 4 0.01
<280 72 13 82 3
V15 PC (cm3) ≥1200 33 9 0.60 40 2 0.69
<1200 51 10 56 5
V30 PC (cm3) ≥900 21 9 0.05 25 5 0.02
<900 63 10 71 2
V40 PC (cm3) ≥750 12 9 0.003 16 5 0.004
<750 72 10 80 2
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3D CRT, three-dimensional conformal radiation; IMRT, intensity-modulated radiotherapy; LB, large bowel; PC, peritoneal cavity; RT, radiotherapy; SB, small bowel; TB, total bowel; V15–V40, volume of bowel getting the specified dose in gray.

Figure 2.

Figure 2.

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Recommended dose–volume histogram for restricting late bowel toxicity ≥grade III within 5%. x-axis, volume receiving 15, 30 and 40 Gy; y-axis, absolute bowel volume (in cubic centimetres).

Patients receiving concurrent chemoradiation

Univariate analysis for patients receiving concurrent chemoradiation (n = 87) is depicted in Table 4. On multivariate analysis, presence of acute grade ≥III toxicity was identified as independent predictors of grade ≥II late bowel toxicity (OR 4.1, 95% CI 1.2–13.1, p < 0.01).

Table 4.

Univariate analysis of treatment-related parameters predicting late bowel toxicity in patients undergoing chemoradiation (n = 87)

Variables Strata (n) Grade ≥II, absent Grade ≥II, present p-value Grade ≥III, absent Grade ≥III, present p-value
Age (years) <48 36 9 0.48 42 3 0.93
≥48 36 6 39 3
Type of hysterectomy Wertheim's 26 4 0.48 54 3 0.40
Simple 46 11 27 3
Type of RT IMRT 44 5 0.02 49 0 0.002
3D CRT 23 10 27 6
Body mass index (kg m−2) <25 37 11 0.12 45 3 0.79
≥25 35 4 36 3
Abdominal surgery Single 53 9 0.30 57 5 0.76
Multiple 3 2 5 0
Co-morbidities Yes 5 2 0.40 5 2 0.01
No 67 13 76 4
Tobacco use Yes 11 1 0.37 11 1 0.83
No 61 14 70 6
Acute grade II Yes 45 12 0.19 51 6 0.06
No 27 3 30 0
Acute grade III Yes 12 7 0.01 14 5 0.0001
No 60 8 67  
V15 SB (cm3) ≥275 13 4 0.44 14 3 0.05
<275 59 11 67 3
V30 SB (cm3) ≥190 14 6 0.08 17 3 0.10
<190 58 9 64 3
V40 SB (cm3) ≥150 14 6 0.08 16 4 0.008
<150 58 9 65 2
V15 LB (cm3) ≥250 8 4 0.11 9 3 0.008
<250 64 11 72 3
V30 LB (cm3) ≥100 23 7 0.27 27 3 0.40
<100 49 8 54 3
V40 LB (cm3) ≥90 18 6 0.23 21 3 0.20
<90 54 9 60 3
V15 TB (cm3) ≥450 16 4 0.71 18 2 0.53
<450 56 11 63 4
V30 TB (cm3) ≥330 11 4 0.28 13 2 0.27
<330 61 11 68 4
V40 TB (cm3) ≥280 11 4 0.28 12 3 0.02
<280 61 11 69 3
V15 PC (cm3) ≥1200 28 6 0.93 32 2 0.76
<1200 44 9 49 4
V30 PC (cm3) ≥900 18 7 0.09 21 4 0.03
<900 54 8 60 2
V40 PC (cm3) ≥750 12 7 0.01 15 4 0.006
<750 60 8 66 2
Open in a new tab

3D CRT, three-dimensional conformal radiation; IMRT, intensity-modulated radiotherapy; LB, large bowel; PC, peritoneal cavity; RT, radiotherapy; SB, small bowel; TB, total bowel; V15–V40, volume of bowel getting the specified dose in gray.

DISCUSSION

In an earlier study8 from our group, we identified V15 SB and V15 LB to be important independent predictors of late toxicity. A recent study9 on 97 patients undergoing adjuvant radiation identified V15–V45 SB dose and identified smoking as an independent risk factor for chronic GI toxicity. Contouring PC is more convenient method of delineating bowel than for SB and LB as their differentiation can be difficult. There is also an inherent delineation inaccuracy of SB and LB which can reach up to 17%.10 Theoretically, PC may also be more representative of the actual bowel dose as it includes all possible volume of internal motion.

The results of the present study verified the predictive ability of V15 SB and V15 LB reported in our earlier study on univariate analysis.8 While the present study also verified the ability of V40 SB to predict acute and late toxicities,9 PC doses only independently predicted acute grade ≥II toxicity, and acute toxicity was the only significant predictor of late toxicity. This is also the first study that conclusively confirms the predictive value of acute toxicity as an independent predictor of late toxicity in patients undergoing adjuvant pelvic radiation. Though our study has limited number of patients, we demonstrated that use of concurrent chemotherapy or treatment technique (IMRT) does not impact late outcomes. None of these factors predicted late toxicity.

The PC dose–volume thresholds identified to be predictive of late toxicity within our study are also more generous than that proposed by Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC)3,8 and an earlier study in patients with rectal cancer.5 This difference could possibly be attributed to amount of intrapelvic bowel in patients with cervical and rectal cancer or type of chemotherapy. It may also be noted that patients with rectal cancer may have inherent bowel symptoms which may attribute to increased bowel toxicity and thereby lowering the dose–volume thresholds. The thresholds identified in this study are derived from actual event data in cervical cancer and may be more applicable in this patient subset.

CONCLUSION

PC doses and acute GI toxicity are independent predictors of late grade ≥III bowel toxicity. The data presented in this study can be used to restrict late bowel injury in patients undergoing adjuvant chemoradiation for cervical cancer and also identify patients who are at risk of developing serious late bowel injury.

FUNDING

This study was supported by the Department of Science and Technology, India; Department of Atomic Energy Clinical Trials Centre, India.

Contributor Information

Supriya Chopra, Email: supriyasastri@gmail.com.

Rahul Krishnatry, Email: supriyasastri@gmail.com.

Tapas Dora, Email: supriyasastri@gmail.com.

Sadhna Kannan, Email: supriyasastri@gmail.com.

Biji Thomas, Email: supriyasastri@gmail.com.

Supriya Sonawone, Email: supriyasastri@gmail.com.

Reena Engineer, Email: supriyasastri@gmail.com.

Siji Paul, Email: supriyasastri@gmail.com.

Reena Phurailatpam, Email: supriyasastri@gmail.com.

Umesh Mahantshetty, Email: supriyasastri@gmail.com.

Shyam Shrivastava, Email: supriyasastri@gmail.com.

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