International Journal of

Radiation Oncology

biology physics

www.redjournal.org

Clinical Investigation: Gynecologic Cancer

Predictors of Grade 3 or Higher Late Bowel Toxicity inPatients Undergoing Pelvic Radiation for Cervical Cancer:Results From a Prospective StudySupriya Chopra, MD,* Tapas Dora, MD,* Anand.N. Chinnachamy, MD,y

Biji Thomas, BSc,* Sadhna Kannan, MSc,z Reena Engineer, DNB,y

Umesh Mahantshetty, MD,y Reena Phurailatpam, DRP,* Siji N. Paul, DRP,*and Shyam Kishore Shrivastava, MDy

*Department of Radiation Oncology, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), TataMemorial Centre, Kharghar, Navi Mumbai, Maharashtra, India; yDepartment of Radiation Oncology, Tata MemorialHospital, Tata Memorial Centre, Parel, Mumbai, Maharashtra, India; and zEpidemiology and Clinical Trials Unit,Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, NaviMumbai, Maharashtra, India

Received Jul 23, 2013, and in revised form Sep 19, 2013. Accepted for publication Nov 8, 2013.

Summary

This study investigated thecorrelation between boweldose volume parameters andgrade 3 or higher latetoxicity in women undergo-ing postoperative radiationfor cervical cancer. The vol-ume of the small and largebowel receiving 15 Gy (V15)was identified as an inde-pendent predictive factor.Restricting small bowel andlarge bowel volume to lessthan 275 cc and 250 cc,respectively, can reduce theincidence of severe late

Reprint requests to: Supriya Chopra, MD, D

Radiation Oncology, ACTREC, Tata Memoria

Mumbai, India 410210. Tel: 912227405113

schopra@actrec.gov.in

Conflict of interest: none.

Int J Radiation Oncol Biol Phys, Vol. 88, No. 3

0360-3016/$ - see front matter � 2014 Elsevie

http://dx.doi.org/10.1016/j.ijrobp.2013.11.214

Purpose: The present study investigates relationship between doseevolume parameters and se-vere bowel toxicity after postoperative radiation treatment (PORT) for cervical cancer.Methods and Materials: From June 2010 to December 2012, a total of 71 patients undergoingPORTwere included. Small bowel (SB) and large bowel (LB) loops were contoured 2 cm abovethe target volume. The volume of SB and LB that received 15 Gy, 30 Gy, and 40 Gy was calcu-lated (V15 SB, V15 LB, V30 SB, V30 LB, V40 SB, V 40 LB). On follow-up, bowel toxicity wasscored using Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. A recie-ver operating characteristic (ROC) curve identified volume thresholds that predicted for grade 3or higher toxicity with highest specificity. All data was dichotomized across these identified cut-off values. Univariate and multivariate analysis was performed using SPSS, version 15.Results: The median patient age was 47 years (range, 35-65 years). Of the 71 patients, 46received image-guided intensity modulated radiation therapy, and 25 received conformal radia-tion (50 Gy in 25 fractions for 5 weeks). Overall, 63 of 71 patients received concurrent chemo-therapy. On a median follow-up of 18 months (range, 8-29 months), grade 2 or higher boweltoxicity was seen in 22 of 71 patients (30.9%) and grade 3 or higher bowel toxicity was seenin 9 patients (12.6%). On univariate analysis, V15 SB <275 cc (PZ.01), V30 SB <190 cc(PZ.02), V40 SB <150 cc (PZ.01), and V15 LB <250 cc (PZ.03), and V40 LB <90 cc(PZ.04) predicted for absence of grade 3 or higher toxicity. No other patient- or treatment-related factors were statistically significant. On multivariate analysis, only V15 SB (PZ.002)and V15 LB (PZ.03) were statistically significant.

NB, Associate Professor,

l Centre, Kharghar, Navi

, 912224177147.; E-mail:

AcknowledgmentsdThe authors acknowledge the Department of

Atomic Energy Clinical Trials Centre (DAE-CTC) for research funding.

T.D. and B.T. receive salary support through DAECTC research funding.

, pp. 630e635, 2014

r Inc. All rights reserved.

Volume 88 � Number 3 � 2014 Predictors of late bowel toxicity 631

bowel toxicity to less than

5%.

Conclusions: V 15 Gy SB and LB are independent predictors of late grade 3 or higher toxicity.Restricting V15 SB and V15 LB to <275 cc and <250 cc can reduce grade 3 or higher toxicityto less than 5%. � 2014 Elsevier Inc.

Introduction

Adjuvant pelvic radiation with or without chemotherapy is rec-ommended in patients with intermediate or high risk factors after aWertheim operation. Postoperative radiation therapy (PORT) re-duces the rate of both local (13.9% vs 20.7%) and distant (2.9% vs8.6%) recurrence (1). Even higher benefit is observed in patientswith high risk factors (1, 2). Surgical extirpation of the uterusresults in adhesions of bowel loop and altered microvasculatureincreasing vulnerability of bowel to the adverse effects of PORT.These changes may severely impair intestinal function if strictureformation occurs (3), thereby leading to serious gastrointestinal(GI) sequelae (4-6). A retrospective study reported a 16.4%incidence of late grade 2 to 4 bowel toxicity among patientstreated with PORT and brachytherapy. A pelvic dose of >54 Gyand age >60 years were identified as risk factors for late boweltoxicity (7). Platinum-based chemoradiation (8-12) further adds totoxicity. Clinically meaningful data can also be derived fromPORT studies for rectal cancer. Long-term follow-up of theUppasla trial reported a 6% incidence of obstruction after surgeryalone and 11% after postoperative radiation (13). An overviewundertaken by Kavanagh et al reported incidence of late smallbowel (SB) perforation of the order of 2% to 9% with 50 Gy ofpelvic radiation therapy (14). However, the risk may be increasedin patients undergoing PORT with brachytherapy and chemo-therapy.

Intensity modulated radiation therapy (IMRT) minimizes thevolumes of irradiated SB (14, 15). A statistically significant cor-relation has been demonstrated between volume of irradiatedbowel and severe acute toxicity (16, 17). Although there are recentstudies (18) that correlate acute toxicity with irradiated bowelvolume, there is a paucity of data regarding correlation of boweldoseevolume histogram (DVH) parameters with late toxicity. Inthe era of increasing use of conformal or IMRT, it will beworthwhile to evaluate correlation of bowel parameters with latebowel toxicity and develop DVH recommendations for mini-mizing bowel toxicity.

Methods and Materials

From January 2010 to December 2012, all patients undergoingadjuvant or salvage pelvic chemoradiation were included. Allpatients signed informed consent forms and were treated withinthe context of institutional review board-approved clinical trials. Auniform methodology for simulation and target delineation wasfollowed (19-21).

Simulation

All patients emptied the bladder and then consumed 500 mL ofwater. Imaging was done after 30 minutes. Patients were posi-tioned supine with arms above the head. Three radio-opaquefiducial markers were placed at laser intersection points on thelower abdomen, and a radio-opaque marker was placed at the

vaginal introitus while obtaining the scan. A contrast-enhancedcomputed tomography (CECT) scan was obtained from the dia-phragm to the mid-thigh at an interslice thickness of 3 mm. Theimage data sets were transferred to Oncentra treatment planningsystem (version 4.1).

Target delineation

Wherever present, gross residual disease was contoured. In pa-tients with no gross residual disease, the vaginal apex wasidentified with the help of silver markers placed before simula-tion. The vaginal apex or residual gross tumor volume wasexpanded anteriorly by 1.5 cm, superiorly by 1 cm, posteriorlyuntil the mesorectal fascia, and laterally until the pelvic muscles.In patients with no residual disease, one-half of the vagina wasincluded, and in patients with gross residual disease, a caudalmargin of 2 to 2.5 cm was used to generate the clinical targetvolume (CTV). An additional 1-cm margin (7 mm posteriorly)was used to generate a planning target volume (PTV) for theprimary. Nodal delineation was done using standard guidelines(22). In addition, lymphoceles and gross lymph nodes wereincluded in the nodal CTV. Nodal CTV was expanded by 5 mmto generate a nodal PTV. A Boolean operation was used toperform the union of nodal and primary PTV to generate the finalPTV. All organs at risk (OARs) except the bowel were delineatedusing standard guidelines (23). Bowel delineation includedcontouring individual bowel loops for the small as well as thelarge bowel (LB). The bowel was delineated up to 2 cm abovethe PTV.

Radiation planning

All patients underwent conformal or image-guided intensity-modulated radiation therapy (IG-IMRT) planning. Those un-dergoing conformal radiation received treatment with a 4-field,multileaf collimeter shaped box field technique, and IG-IMRTtreatment was executed using tomotherapy. During planapproval, all care was taken to cover 95% of the target with 95%of the prescription dose. Care was also taken to reduce the boweldose through beam weighting during conformal planning. Dur-ing IMRT planning, dose constraints were used to restrict thevolume of SB receiving 15 and 40 Gy (V15/V40 SB) to <190 ccand <100 cc, respectively. All patients received 50 Gy in 25fractions for 5 weeks with or without weekly cisplatin (40 mg/m2). This was followed by brachytherapy. For the purpose of thepresent study, for each patient the absolute volume of SB andLB and that receiving 15 Gy (V15), 30 Gy (V30), and 40 Gy(V40) was recorded. All patients were treated with a full bladderregimen. For those undergoing conformal treatment, onceweekly electronic portal or cone beam imaging was performedto ensure bony match. Patients undergoing IG-IMRT withtomotherapy underwent a daily pretreatment megavoltage CT(MVCT) scan.

Chopra et al. International Journal of Radiation Oncology � Biology � Physics632

Toxicity recording

Common Terminology Criteria for Adverse Events (CTCAE),version 3.0, (24) has been tested for reliability and validity withinour population (25). All patients in the present study completedthe gastrointestinal (GI)-specific module of CTCAE at baseline,weekly during treatment, and then subsequently at each 3-monthlyfollow-up. If patients presented with serious GI adverse events,then a CTCAE questionnaire was also filled out at the time of theadverse event. Patients were censored on disease progression.

Statistical analysis

Tne Statistical Package for Social Sciences (SPSS), version 15.0,was used for statistical analysis. On follow-up, the worst grade ofbowel toxicity (excluding proctitis) was recorded. Data werecategorized to obtain 2 groups, namely, grade 0 to 2 toxicity andgrade 3 or higher toxicity. An ROC curve was used to identifythreshold levels of SB, LB (V15. V30, V40) that predict forpresence of late grade 3 GI toxicity with the highest specificity.Data were categorized across these identified cut-offs for univar-iate analysis. In addition, other factors affecting late toxicity (eg,type of surgery, age, use of chemotherapy, salvage, or adjuvantradiation) were also included. Multivariate analysis was per-formed with binary logistic regression using backward conditionalmethod. Using the SB and LB thresholds identified as being sig-nificant on statistical analysis, a predictive DVH was generated.

Results

Patient and treatment characteristics

A total of 71 patients were included in the present study. Themedian age was 47 years (range, 35-65 years). Of the patients, 46(64.8%) received tomotherapy-based IMRT and 25 (35.2%)received 3-dimensional conformal radiation. Overall, 63 of the 71patients (88.7%) received concurrent weekly cisplatin. All patientsincluded in this study received vaginal brachytherapy. Overall, thevolume of SB and LB was 283 � 168 cc and 173 � 138 cc,respectively. The V15, V30, and V40 for the SB, LB, and TB aredetailed in Table 1.

Late toxicity

At a median follow-up of 18 months (range, 8-29 months), grade 2or higher bowel toxicity (excluding proctitis) was seen in 22 of 71

Table 1 Doses received by the small and large bowels

Organ Mean (cc) Median (cc) Range (cc)

Small bowel (cc) 283 257 12-712V15 218 199 2-496V30 166 136 20-491V40 127 98 14-482

Large bowel (cc) 172 119 16-602V15 163 143 2-618V30 108 83 3-540V40 79 45 2-518

patients (30.9%), and grade 3 or higher bowel toxicity was seen in9 patients (12.6%). The details of all GI toxicities during follow-up are detailed in Table 2. As few patients had more than 1 type ofGI toxicity, the event rate in Table 2 exceeds the total number ofpatients with toxicity. The median time to late grade 3 boweltoxicity was 8 months (range, 3-9 months). As shown in Table 2,diarrhea (5.6%) and obstruction (5.6%) were the most commongrade 3 toxicities. Rectal bleeding and ulcer (CTCAE grade 3/4)was seen in 2.8% of patients; however, it was noncontributorytoward the late bowel toxicity analysis. Lower abdominal pain(8.5%) was the most common grade 2 bowel toxicity, followed byrectal bleeding (5.6%) and anorexia (4.2%).

Univariate/Multivariate analysis

Grade 2 toxicityOn univariate analysis, V30 SB (PZ.05), V40 SB (PZ.004), andV15 LB (PZ.03) predicted for late grade II bowel toxicity.Restricting V30 and V40 SB to <190 cc and <150 cc and V15 LBto <250 cc could reduce the incidence of grade 2 toxicity fromgreater than 25% to 10%. No other patient- and treatment-relatedfactors contributed toward grade 2 late bowel toxicity. However,on multivariate analysis, none of the factors were statisticallysignificant.

Grade 3 or higher toxicityOn univariate analysis, V15 SB (PZ.01), V30 SB (PZ.02), V40SB (PZ.01), V15 LB (PZ.03), and V40 LB (PZ.04) predictedfor late grade 3 bowel toxicity. Each dose level except V30 LBwas statistically significant. Restricting V 15, V30, and V40 SB to<275 cc, 190 cc and <150 cc and V15, V30, and V40 LB to <250cc, <100 cc, and <90 cc could reduce the incidence of grade 3toxicity from 20% to 5%. No other patient- and treatment-relatedfactors contributed toward late bowel toxicity. On multivariateanalysis, only V15 SB (PZ.002) and V15 LB (PZ.03) wereidentified to be statistically significant. Using the doseevolumethresholds identified in this study, a model DVH was generated inwhich restricting bowel parameters within the area under therecommended curve could restrict grade 3 or higher bowel toxicityto 5%. (Fig. 1)

Discussion

Although there are a few publications (26, 27) that address therelationship between irradiated bowel volume and acute toxicity,there are no DVH recommendations for preventing serious latebowel sequelae in women undergoing pelvic radiation for gyne-cological malignancies. Roeske et al (26) evaluated correlationbetween irradiated bowel and acute GI toxicity in women withgynecological cancers (nZ50). In that study, bowel was contouredas the outside surface of the SB (neither as individual loops nor asperitoneal space). The authors concluded that the volume of SBreceiving 100% of the dose (V100% or V45 Gy) is the mostpredictive factor and should be restricted to <195 cc. Huang et al(27) evaluated DVH correlates of acute toxicity in women un-dergoing pelvic radiation with and without prior abdominal sur-gery (nZ80). SB loops were contoured only within the irradiatedfield. The authors concluded that although V15 Gy (or 40% dose)predicts for acute bowel toxicity in patients undergoing pelvicradiation without prior surgery, V40 Gy (100% dose) is more

Table 2 Incidence and grade of each gastrointestinal toxicity subscale (CTCAE, version 3.0)

Toxicity Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Grade 5

Diarrhea 60 (84.5%) 5 (7%) 2 (2.8%) 4 (5.6%) 0 0Obstruction 66 (92.9%) 1 (1.4%) 0 (0%) 4 (5.6%) 0 0Hemorrhage 64 (90.1%) 1 (1.4%) 4 (5.6%) 1 (1.4%) 1 (1.4%) 0Distension 29 (40.8%) 40 (56.3%) 2 (2.8%) 0 0 0Anorexia 54 (76.1%) 14 (19.7%) 3 (4.2%) 0 0 0Malabsorption 70 (98.6%) 1 (1.4%) 0 0 0 0Nausea 61 (85.9%) 10 (14.1%) 0 0 0 0Pain 52 (73.2%) 13 (18.3%) 6 (8.5%) 0 0 0Vomiting 68 (95.8%) 3 (4.2%) 0 0 0 0Constipation 65 (91.5%) 6 (8.5%) 0 0 0 0Ulcer 71 (100%) 0 0 0 0 0Perforation 70 (98.4%) 0 0 0 0 1 (1.4%)Stricture 71 (100%) 0 0 0 0 0

Abbreviation: CTCAE Z Common Toxictiy Criteria for Adverse Events.

Volume 88 � Number 3 � 2014 Predictors of late bowel toxicity 633

predictive in patients who have undergone previous abdominalsurgery.

Baglan et al (17) evaluated the incidence of acute boweltoxicity in a cohort of patients undergoing 5-fluorouracuil-basedchemoradiation (nZ40) for rectal cancer. The authors contouredindividual bowel loops within the irradiated field and reported asteep doseevolume effect between 10 and 15 Gy. The authorsreported that when V15 Gy was restricted to <150 cc, then nopatient developed serious grade 3 acute toxicity. Peak toxicity wasobserved at 20 to 30 Gy (ie, 4-5 days after receiving 15 Gy in mostof the patients). Grade 3 or higher toxicity could be avoided byrestricting V15 to <150 cc. Of those patients receiving 15 Gy to150 to 299 cc of bowel volume, 40% developed grade 2 or highertoxicity. No impact of type of surgery (Werthiem operation orsimple hysterectomy) was noted on the bowel toxicity. As almostall patients received 5-fluorouracil, the contribution of 5-fluorouracil toward GI toxicity could not be assessed. Similarly,the impact of disease extent within rectum could have contributedto the GI toxicity scoring and could not be assessed separately. Inanother large study (nZ152) of rectal cancer patients undergoingpreoperative or adjuvant chemoradiation. Robertson et al (28)proposed that acute grade 3 acute GI toxicity could be reducedto less than 11% if V15 were restricted to 130 cc.

More recently, Banerjee et al (29) evaluated doseevolumerelationships in patients undergoing neoadjuvant chemoradiation

Fig. 1. Recommended doseevolume histogram. Restrictingsmall bowel and large bowel volume doses within the recom-mended area under curve can restrict late bowel toxicity to within5%.

for rectal cancers and observed that the incidence of grade 3 orhigher toxicity could be reduced to 10% using a V15 cut-off of<275 cc when the SB was contoured using individual bowelloops and <830 cc when contouring the peritoneal space. Thisvolume constraint was much higher than that proposed byKavanagh et al (30). This difference could be attributed to dif-ference in contoured volume of the SB. Unlike Banerjee et al,who uniformly contoured the SB 1.5 cm above the radiation field(which could account more accurately for the volume receivinglow-dose radiation), the earlier studies contoured the SB onlywithin the pelvic field.

The only available data that correlate doseevolume parametersand late bowel toxicity are for patients undergoing postoperativeradiation for rectal cancer. The bowel volume in this studywas derived using barium films. Although no correlation fordoseevolume parameters could be demonstrated for obstruction(the incidence of which was 11%), the volume threshold of 328 ccwas identified for chronic diarrhea (31).

Quantec recommendations for preventing bowel toxicity (30)based on data from Baglan et al (17), Robertson et al (16, 28),and Roeske et al (26) suggest that the absolute volume of SBreceiving 15 Gy should be restricted to <120 cc (if individualbowel loops are outlined) or the volume receiving >45 Gy shouldbe <195 cc (if the entire volume of peritoneal space in which theSB can move is delineated) to minimize severe acute toxicity andlikely late toxicity risk, although this correlation is not established.These constraints may be achievable if only part of the bowel (orthat within pelvic field is delineated). However if the bowel issystematically contoured up to 1.5 to 2 cm above the pelvic field(regions receiving low-dose radiation), then V15 constraints forindividual bowel loops are difficult to obtain even with IMRTplanning. Similarly, the peritoneal space recommendations arebased on the study by Roeske et al, in which the authors delin-eated the outer surfaces of bowel loops, rather than true theperitoneal space or bowel bag, and are difficult to achieve.

Our study is the first to investigate DVH metrics with grade 3or higher late bowel injury after pelvic radiation for gynecologicalcancers. The late grade 3 event rate of 12.6% in the present studyis similar to that observed in adjuvant rectal cancer studies (32).Using a stringent contouring methodology, our study ensured thatall bowel receiving low and high dose was delineated duringtreatment planning. Instead of the bowel bag, we chose to contour

Table 3 Univariate analysis of patient- and treatment-related factors

Strata (n)Grade 2 or

higher absent (%)Grade 2 or

higher present (%) P value

Grade 3or higherAbsent (%)

Grade 3or higher

Present (%)P

value

Age (y) �47 (39) 82% 18% .30 84.6% 15.4% .08<47 (32) 90.6% 9.4% 96.8% 3.2%

Type of surgery Wertheim (23) 91.3% 8.7% .25 91.3% 8.7% .15Simple (48) 83.3% 16.7% 89.5% 9.5%

Concurrent chemotherapy Yes (63) 85.7% 14.3% .89 90.4% 9.6% .79No (8) 87.5% 12.5% 87.5% 12.5%

Indication for RT Adjuvant (51) 82.3% 17.7% .16 88.2% 11.8% .39Salvage (20) 95% 5% 95% 5%

SB volume (cc) �300 (31) 83.8% 16.2% .66 87% 13% .44<300 (40) 87.5% 12.5% 92.5% 17.5%

LB volume (cc) �170 (29) 79.3% 20.7% .18 82.7% 17.3% .08<170 (42) 90.4% 9.6% 95.2% 4.8%

V15 SB (cc) �275 (15) 73.3% 26.7% .11 73.3% 26.7% .01<275 (56) 89.2% 10.8% 94.6% 5.4%

V30 SB (cc) �190 (24) 75% 25% .05 79.1% 21.9% .02<190 (47) 91.4% 8.6% 95.7% 4.3%

V40 SB (cc) �150 (22) 68.1% 31.9% .004 77.2% 22.8% .01<150 (49) 93.8% 6.2% 95.9% 4.1%

V15 LB (cc) �250 (17) 70.5% 29.5% .03 76.4% 23.6% .03<250 (54) 90.7% 9.3% 94.4% 5.6%

V30 LB (cc) �100 (28) 78.5% 21.5% .15 82.1% 17.9% .06<100 (43) 90.6% 9.4% 95.3% 4.7%

V40 LB (cc) �90 (26) 76.9% 23.1% .09 80.7% 19.3% .04<90 (45) 91.1% 8.9% 95.5% 4.5%

Chopra et al. International Journal of Radiation Oncology � Biology � Physics634

individual bowel loops, as we believed that contouring of bowelloops would provide greater accuracy in correlation. We censoredpatients at recurrence, such that symptoms related to recurrence orsalvage treatment do not contribute to the analysis toxicity.Proctitis was excluded from statistical analysis, as it classifies as a“rectal” rather than a “bowel event” Univariate analysis identifiedthat each of SB and LB metrics (V15, V30, and V40 Gy)contribute toward grade 3 toxicity. Restricting these metrics belowthresholds listed in Table 3 can reduce the incidence of severe lateinjury to 5%. On the basis of these thresholds, we propose a modelDVH for SB and LB. Restricting irradiated SB within the pro-posed area under curve can reduce the incidence of grade 3 boweltoxicity to less than 5%.

As the volume of SB and LB receiving high and low doses areinterdependent, we performed multivariate analysis to assess themost predictive factor for preventing serious late toxicity. Onmultivariate analysis, V15 SB <275 cc and V15 LB <250 ccpredicted for reduced incidence of serious bowel toxicity. As ourV15 thresholds are similar to that proposed by Banerjee et al (29),it is likely that the same recommendations could be used toprevent serious acute toxicity as well. The doseevolume con-straints proposed by our study are different (and more generous)than those proposed in other series, including QuantitativeAnalysis of Normal Tissue Effects in the Clinic (QUANTEC)recommendations (14, 30); however, we believe that our meth-odology is more stringent and accurate in terms of delineation ofbowel, and our results may help in refining the existing QUAN-TEC doseevolume recommendations for the SB. Furthermore,using a complete bowel delineation methodology, the constraintsproposed by QUANTEC are difficult to achieve even with IMRTplanning.

Although we used stringent methodology, there could besome overlap in delineating SB and LB. However, as each SBand LB were independently predictive, small variations indelineation are unlikely to cause any major change in our sta-tistical conclusions. It is also likely that instead of SB and LBloops, the total bowel volume delineated as a single structurecould predict for late toxicity. However, as most of the latebowel obstructions occur in the ileum, we restricted ourselves toanalyzing these parameters separately. This article has not re-ported a comparison of individual bowel loop and peritonealspace constraints. This is part of an ongoing investigation andwill be published separately.

The technique of radiation delivery (IMRT vs 3DCRT) directlyaffects the bowel dose and could possibly be an independentpredictor of late bowel toxicity. However, as the present study isneither randomized nor a matched pair analysis, we refrained fromusing technique as a statistical variable. The impact of the radia-tion technique (IMRT) on late SB toxicity is currently the subjectof an ongoing, phase 3, randomized trial at ACTREC, Tata Me-morial Centre (21, 32). Although the event rate in the presentstudy is in keeping with the published literature, the follow-upperiod is relatively short, and it is likely that further follow-upmay redefine our doseevolume recommendations.

Conclusion

In conclusion, the volume of the SB and LB receiving low doses(15 Gy) are independent predictors of grade 3 or higher boweltoxicity during pelvic radiation treatment. Restricting the volumereceiving 15 Gy to <275 cc and <250 cc can reduce the incidence

Volume 88 � Number 3 � 2014 Predictors of late bowel toxicity 635

of grade 3 or higher toxicity in women undergoing postoperativeradiation for cervical cancer.

References

1. Rotman M, Sedlis A, Piedmonte MR, et al. A phase III randomized

trial of postoperative pelvic irradiation in stage IB cervical carcinoma

with poor prognostic features: Follow-up of A Gynecologic Oncology

Group study. Int J Radiat Oncol Biol Phys 2006;65:169-176.

2. Sedlis A, Bundy BN, Rotman MZ, et al. A randomized trial of pelvic

radiation therapy versus no further therapy in selected patients with

stage IB carcinoma of the cervix after radical hysterectomy and pelvic

lymphadenectomy: A Gynecologic Oncology Group study. Gynecol

Oncol 1999;73:177-183.

3. Yeoh EK, Horowitz M. Radiation enteritis. Surg Gynecol Obstet 1987;

165:373-379.

4. Corn BW, Lanciano RM, Greven KM, et al. Impact of improved

irradiation technique, age, and lymph node sampling on the severe

complication rate of surgically staged endometrial cancer patients: A

multivariate analysis. J Clin Oncol 1994;12:510-515.

5. Perez CA, Breaux S, Bedwinek JM, et al. Radiation therapy alone in

the treatment of carcinoma of the uterine cervix. II. Analysis of

complications. Cancer 1984;54:235-246.

6. Roeske JC, Mundt AJ, Halpern H, et al. Late rectal sequelae following

definitive radiation therapy for carcinoma of the uterine cervix: A

dosimetric analysis. Int J Radiat Oncol Biol Phys 1997;37:351-358.

7. Chen S-W, Liang J-A, Yang S-N, et al. Radiation injury to intestine

following hysterectomy and adjuvant radiotherapy for cervical cancer.

Gynecol Oncol 2004;95:208-214.

8. Keys HM, Bundy BN, Stehman FB, et al. Cisplatin, radiation, and

adjuvant hysterectomy compared with radiation and adjuvant hyster-

ectomy for bulky stage IB cervical carcinoma. N Engl J Med 1999;

340:1154-1161.

9. Morris M, Eifel PJ, Lu J, et al. Pelvic radiation with concurrent

chemotherapy compared with pelvic and para-aortic radiation for

high-risk cervical cancer. N Engl J Med 1999;340:1137-1143.

10. Peters WA 3rd, Liu PY, Barrett RJ 2nd, et al. Concurrent chemo-

therapy and pelvic radiation therapy compared with pelvic radiation

therapy alone as adjuvant therapy after radical surgery in high-risk

early-stage cancer of the cervix. J Clin Oncol 2000;18:1606-1613.

11. Rose PG, Bundy BN, Watkins EB, et al. Concurrent cisplatin-based

radiotherapy and chemotherapy for locally advanced cervical cancer.

N Engl J Med 1999;340:1144-1153.

12. Whitney CW, Sause W, Bundy BN, et al. Randomized comparison

of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to

radiation therapy in stage IIB-IVA carcinoma of the cervix with

negative para-aortic lymph nodes: A Gynecologic Oncology Group

and Southwest Oncology Group study. J Clin Oncol 1999;17:1339-

1348.

13. Frykholm GJ, Glimelius B, Pahlman L. Preoperative or postoperative

irradiation in adenocarcinoma of the rectum: Final treatment results of

a randomized trial and an evaluation of late secondary effects. Dis

Colon Rectum 1993;36:564-572.

14. Kavanagh BD, Schefter TE, Wu Q, et al. Clinical application of

intensity-modulated radiotherapy for locally advanced cervical cancer.

Semin Radiat Oncol 2002;12:260-271.

15. Portelance L, Chao KS, Grigsby PW, et al. Intensity-modulated radi-

ation therapy (IMRT) reduces small bowel, rectum, and bladder doses

in patients with cervical cancer receiving pelvic and para-aortic irra-

diation. Int J Radiat Oncol Biol Phys 2001;51:261-266.

16. Robertson JM, Lockman D, Yan D, et al. The dose-volume relation-

ship of small bowel irradiation and acute grade 3 diarrhea during

chemoradiotherapy for rectal cancer. Int J Radiat Oncol Biol Phys

2008;70:413-418.

17. Baglan KL, Frazier RC, Yan D, et al. The dose-volume relationship of

acute small bowel toxicity from concurrent 5-FU-based chemotherapy

and radiation therapy for rectal cancer. Int J Radiat Oncol Biol Phys

2002;52:176-183.

18. Banerjee R. Small bowel dose parameters predicting grade �3 acute

toxicity in rectal cancer patients treated with neoadjuvant chemo-

radiation. Int J Radiat Oncol Biol Phys 2013;85:1225-1231.

19. Chopra S. MR-PET guided biologically optimised interstitial

brachytherapy (MR-PET Brachy). ClinicalTrials.gov Identifier:

NCT01391065 2011.

20. Engineer R. Tomotherapy in postsurgery recurrent carcinoma cervix.

ClinicalTrials.gov Identifier: NCT01117402 2010.

21. Chopra S. Tomotherapy vs conventional radiation for adjuvant pelvic

RT in Ca cervix (PARCER). ClinicalTrials.gov Identifier:

NCT01279135 2011.

22. Taylor A, Rockall AG, Reznek RH, et al. Mapping pelvic lymph

nodes: Guidelines for delineation in intensity-modulated radiotherapy.

Int J Radiat Oncol Biol Phys 2005;63:1604-1612.

23. Gay HA, Barthold HJ, O’Meara E, et al. Pelvic normal tissue con-

touring guidelines for radiation therapy: A Radiation Therapy

Oncology Group consensus panel atlas. Int J Radiat Oncol Biol Phys

2012;83:e353-e362.

24. Trotti A, Colevas AD, Setser A, et al. CTCAE v3.0: Development of a

comprehensive grading system for the adverse effects of cancer

treatment. Semin Radiat Oncol 2003;13:176-181.

25. Chinnachamy AN, Chopra S, Krishnatry R, et al. Evaluation of

interobserver and interscale agreement in assessing late bowel toxicity

after pelvic radiation in patients with carcinoma of the cervix. Jpn J

Clin Oncol 2013;43:508-514.

26. Roeske JC, Bonta D, Mell LK, et al. A dosimetric analysis of

acute gastrointestinal toxicity in women receiving intensity-

modulated whole-pelvic radiation therapy. Radiother Oncol 2003;

69:201-207.

27. Huang EY, Sung CC, Ko SF, et al. The different volume effects of

small-bowel toxicity during pelvic irradiation between gynecologic

patients with and without abdominal surgery: A prospective study with

computed tomography-based dosimetry. Int J Radiat Oncol Biol Phys

2007;69:732-739.

28. Robertson JM, Sohn M, Yan D. Predicting grade 3 acute diarrhea

during radiation therapy for rectal cancer using a cutoff-dose logistic

regression normal tissue complication probability model. Int J Radiat

Oncol Biol Phys 2010;77:66-72.

29. Banerjee R, Chakraborty S, Nygren I, et al. Small bowel dose param-

eters predicting grade � 3 acute toxicity in rectal cancer patients treated

with neoadjuvant chemoradiation: An independent validation study

comparing peritoneal space versus small bowel loop contouring tech-

niques. Int J Radiat Oncol Biol Phys 2013;85:1225-1231.

30. Kavanagh BD, Pan CC, Dawson LA, et al. Radiation dose-volume

effects in the stomach and small bowel. Int J Radiat Oncol Biol

Phys 2010;76:S101-S107.

31. Letschert JG, Lebesque JV, de Boer RW, et al. Dose-volume corre-

lation in radiation-related late small-bowel complications: A clinical

study. Radiother Oncol 1990;18:307-320.

32. Chopra S, Engineer R, Mahantshetty U, et al. Protocol for a phase III

randomised trial of image-guided intensity modulated radiotherapy

(IG-IMRT) and conventional radiotherapy for late small bowel

toxicity reduction after postoperative adjuvant radiation in Ca cervix.

BMJ Open 2012;2.