Brachytherapy 8 (2009) 240e247

Image-guided intracavitary high-dose-rate brachytherapyfor cervix cancer: A single institutional experience with

three-dimensional CT-based planning

Brian Wang1, Alexander Kwon2, Yunping Zhu2, Inhwan Yeo2, Clarissa F. Henson3,*1Department of Radiation Oncology, University of Utah, Salt Lake City, UT

2Department of Radiation Oncology, Cooper University Hospital, Camden, NJ3Department of Radiation Oncology, Trinitas Comprehensive Cancer Center, Elizabeth, NJ

ABSTRACT PURPOSE: To evaluate and report volumetric

Received 21 May

accepted 21 October

* Corresponding

Williamson Street, Tr

07207. Tel.: þ1-908-

E-mail address: c

1538-4721/09/$ e see

doi:10.1016/j.brach

dose specification of clinical target volume (CTV)and organs at risk with three-dimensional CT-based brachytherapy. In this study, we analyzed CTVvolumes and correlated the dose specification from CT-based volumes with doses at classical pointA and International Commission on Radiation Units and Measurements (ICRU) points.METHODS AND MATERIALS: Ten patients who underwent definitive high-dose-rate brachyther-apy for cervical cancer between May 2006 and March 2007 were retrospectively identified for this study.Each patient underwent five intracavitary insertions with CT-compatible ring and tandem applicators usinga universal cervical Smit sleeve. Dose of 6.0 Gy per fraction was prescribed to the 100% isodose line. Thedose distribution was modified using the feature of ‘‘geometry optimization’’ to achieve maximum CTVcoverage and to spare the organs at risk. The minimal doses for most irradiated 2, 1, 0.1 cm3 of bladder(DBV2 , DBV1, and DBV0.1) and rectum (DRV2, DRV1, and DRV0.1) were determined from doseevolume histograms and were compared with the doses estimated at the ICRU reference points.RESULTS: The mean CTVof the 10 patients had a shrinkage trend over the five fractions, with a meanof 77.4 cm3 from the first fractions and a mean of 65.5 cm3 from the last fractions (r 5�0.911,p 5 0.031). CTV volumes directly correlated with dose to point A (r 5 0.785, p 5 0.007). Eight of10 patients achieved an average dose received by at least 90% of volume (D90) >6.0 Gy. For bladder,the doses determined from the 3-dimensional (3D) plan correlated significantly with the doses to theICRU reference bladder point, for example, DBV2 (r 5 0.668, p!0.001), DBV1 (r 5 0.666,p!0.001), and DBV0.1 (r 5 0.655, p!0.001). However, for rectum, the estimated doses to the ICRUreference rectal point did not correlate significantly with doses determined from 3D plan, for example,DRV2 (r 5 0.251, p 5 0.079), DRV1 (r 5 0.279, p 5 0.049), and DBV0.1 (r 5 0.282, p 5 0.047).CONCLUSIONS: Our experience showed that excellent dose coverage of CTV can be achievedwith image-guided CT-based planning with geometric optimization although maximal sparing ofrectum was not achieved. Careful dose constraints and standardization of D90 should be consideredwhen optimizing doses to target tissues such that normal tissue constraints can be met. � 2009Published by Elsevier Inc on behalf of American Brachytherapy Society.

Keywords: HDR; Brachytherapy; Image guidance; Cervix cancer

Introduction

Intracavitary brachytherapy (ICBT) is an essential compo-nent in the curative treatment of cervical cancer. Traditionaldose prescriptions and treatment planning based on ICRU

2008; received in revised form 17 October 2008;

2008.

author. Department of Radiation Oncology, 225

initas Comprehensive Cancer Center, Elizabeth, NJ

994-9727; fax: þ1-908-994-8725.

henson@trinitas.org (C.F. Henson).

front matter � 2009 Published by Elsevier Inc on behalf

y.2008.10.004

reference points rely on 2-dimensional (2D) imaging withorthogonal radiographs, which provide limited informationon normal tissue anatomy and target volume (1). The adequacyof this planning approach has been questioned due to poten-tially insufficient dose coverage of actual tumor volume andinaccuracy of ICRU reference points in estimating dose tonormal organs (2e9). Furthermore, several studies haveshown that traditional ICRU reference points underestimatedose to normal organs when compared to CT-based 3-dimen-sional (3D) imaging (10, 11).

of American Brachytherapy Society.

241B. Wang et al. / Brachytherapy 8 (2009) 240e247

The introduction of CT/MRI compatible high-dose-rate(HDR) applicators, has allowed for 3D treatment planningand the ability to better delineate target volumes fromsurrounding normal structures (12e18). With afterloadingHDR brachytherapy and 3D anatomic imaging, dose opti-mization can be performed by varying the source positionand dwell times. This promises to offer enhancement ofthe therapeutic ratio between maximizing doses to targettissues and minimizing doses to normal structures (2e6,19e24). In a study by Lindegaard et al., 16 of 21 patientswho underwent MRI-guided HDR brachytherapy with 3Ddose optimization achieved greater target coverage andnormal tissue sparing with dose received by at least 90%of volume (D90) O85 Gy and minimal dose to 2 cc ofbladder and rectum/sigmoid was kept to !90 and!75 Gy, respectively, whereas only 3 of 21 patients metthese constraints with two-dimensional planning (25).Recent studies have shown that ICRU bladder referencepoints underestimate dose to 2 cm3 of bladder, whereasthe rectal ICRU point has shown greater correlation withdose to 2 cm3 of rectum determined by CT or MRI (26).

Researchers at M.D. Anderson found that the ICRUbladder reference point was an unacceptable surrogate forthe maximal radiation dose delivered to the bladder duringICBT of cervical cancer. In this study, the minimal dose to2 cc of the bladder was found to be greater than the ICRUdose by as much as 3.5-fold, which has been supported bythe findings of other investigators (10).

At Cooper University Hospital, we used CT-compatibleapplicators and obtained 3D images for treatment planningto obtain doseevolume information for tumor target,bladder, and rectum. Although treatment outcome and eval-uation of toxicity is the future investigational objective, inthis study our goal was to evaluate and report clinical targetvolume (CTV) changes during low-dose-rate (LDR) treat-ment, its correlation with point A, volumetric dose specifi-cation of CTV, and organs at risk. In this study, we

Table 1

A summary of tumor characteristics and previous pelvic external radiotherapy of 1

brachytherapy

Subject

# Age (years) Clinical stage) Pathology

Pelvic

dose (

1 51 IIB SCC 50.4

2 34 IIA Adeno 50.4

3 29 IIB SCC 50.4

4 37 IIB SCC 46.2

5 50 IIIB SCC 45.0

6 57 IB1 SCC 45.0

7 53 IB2 SCC 45.0

8 48 IB2 SCC 50.4

9 31 IIB SCC 50.4

10 47 IB1 SCC/

Adeno

50.4

Abbreviations: HDR 5 high dose rate; SCC 5 squamous cell carcinoma;

XRT 5 external radiation therapy; Gy 5 gray.) International Federation of Gynecologists and Obstetricians (FIGO) stagin

correlated the dose specification from the CT-basedapproach with doses at classical point A and ICRU points.

Methods and materials

Patient selection

With approval from the Institutional Review Board(RP#07-048EX) at Cooper University Hospital, 10 patientswho underwent concurrent chemoradiation therapy forcervical cancer between May 2006 and March 2007 wereretrospectively identified for this study. Table 1 summarizesthe tumor characteristics, pelvic external radiotherapydoses, HDR nominal prescription doses, and LDR equiva-lent doses. The median age of the patients was 48.0 years(range, 29.3e57.7). Tumor histologies were as follows:eight squamous cell carcinomas, one adenocarcinoma,and one adenosquamous carcinoma of the cervix. Patientshad FIGO stage IB1 through IIIB disease and each patientreceived concurrent weekly cisplatin chemotherapy duringthe external beam portion of radiotherapy.

ICBT treatment technique

Each patient underwent five ICBT insertions with CT-compatible ring and tandem using a universal cervical Smitsleeve. During the fourth or fifth week of external beamradiation therapy (EBRT), a universal Smit sleeve appli-cator was surgically placed into the cervix. All patientsreceived five insertions separated by a minimum of 48 h.Patients were offered Actiq (Fentanyl) and Ativan (Loraze-pam) before applicator insertion for pain control and seda-tion. The length and angle of the tandem applicator wasdetermined based on uterine sounding at the time of Smitsleeve insertion. The applicator ring diameters ranged from2.6 to 3.4 cm and was determined by the patient’s anatomyat the time of HDR procedure. An appropriate rectal blade

0 patients with gynecologic tumors who received 3D CT image-based HDR

XRT

Gy)

Dose to

parametrium (Gy)

HDR nominal

dose (Gy)

LDR equivalent

dose (Gy)

57.6 30 40

NA 30 40

55.8 29 39

56.0 30 40

57.6 30 40

NA 30 40

NA 30 40

55.8 30 40

57.6 30 40

NA 30 40

Adeno 5 adenocarcinoma; SCC/Adeno 5 adenosquamous carcinoma;

g.

242 B. Wang et al. / Brachytherapy 8 (2009) 240e247

was attached to the applicator system; however, in the eventthat a rectal blade could not be accommodated by thepatient, nonradiopaque gauze was placed in the vagina bothanteriorly and posteriorly to the applicator system todisplace normal tissues. The applicator system was securedto the patient with an external pelvic belt and the patientthen underwent CT imaging in the supine position. For non-bulky lesions, the first brachytherapy insertion beganconcurrently during the fourth week of EBRT and was per-formed weekly during EBRT and then twice weekly aftercompletion of EBRT. For larger tumors, the first HDRinsertion began during the fifth week to allow for greatertumor shrinkage. MicroSelectron-HDR automated after-loading system (Nucletron BV, Veenendaal, TheNetherlands) was used for the intracavitary treatment.

Fig. 1. Reconstructed 3D CT scans of AP view for the ring and tan-

dem treatment. Abbreviations: BR 5 Right point B; BL 5 Left point B;

AR 5 Right point A; AL 5 Left point A.

3D image-based planning

After placement and immobilization of applicators, CTimages were acquired using 3-mm thick slices on an AcQ-sim CT scanner (Philips Medical Systems, Best,Netherlands). Images were then transferred to PLATO plan-ning system with organ contours of CTV, bladder, andrectum. A look-up table was generated at the time ofcommissioning for the distance from the first source loca-tions to the tip of the applicators, which were determinedby X-rayebased radiography with dummies for each setof the applicators. Using this look-up table, the applicatorswere reconstructed by selecting and tracking on the CTimages. Sources were initially loaded evenly on both thering and the tandem in the CTV with two extra dwell posi-tions (1 cm). Isodose lines were dynamically ‘‘pulled’’using the feature of geometry optimization and a dose of6.0 Gy was prescribed to the 100% isodose. After thegeometry optimization, the sources will be turned on oroff and weighted automatically at each dwell locations.The CTV included all gross tumor determined by clinicalexamination and CT findings, and all normal cervix andat risk uterus extending the length of the tandem. Point A(defined at 2 cm superior to the cervical os and 2 cm lateralto the tandem) was used as the initial starting point beforegraphic optimization. Point B followed the same definitionof point A except 5 cm lateral to the uterine tandem. Thebladder and rectal points were located on axial view ofCT scan based on ICRU definition. For bladder, the centralcut on CT was used. For rectum, the CT through the middleof the ring applicator was used. The posterior edge of theplastic cover was considered as the posterior vaginal wallas we did not used any packing outside the cover. Theentire bladder organ was contoured and every patient hada Foley balloon in place with empty bladder. Similarly,the entire rectal organ was contoured from anus to therecto-sigmoid flexure. For each ICBT application, the dosesfrom 3D plan were derived from the doseevolume histo-grams as the minimal dose for most irradiated 2, 1,0.1 cm3 of the bladder or the rectum. These doses were

compared with the doses at the ICRU reference points. Itis noted that MRI examination was not routinely part ofthe patient’s initial work-up and as such was not routinelyused as part of our treatment planning.

Statistical analysis

We evaluated two-tailed Pearson correlations for CTV vs.fraction, CTV vs. point A dose, bladder dose at ICRU pointvs. bladder doses from 3D plan, and rectum dose at ICRU pointvs. rectal doses from 3D plan. The data were analyzed by SPSSSoftware Version 15.0.1 (SPSS Inc., Chicago, IL). We calcu-lated and presented the r-value, which indicates strength anddirection (�) of the correlation, and the p-value, which is theprobability for an r-value of this size just by chance.

Results

CTV volume and its correlation to point A dose

Figure 1 depicts the 3D reconstructed CT scans of anteriorposterior (AP) view for the ring and tandem treatment. Themean CTV was 72.1 cm3, ranging from 60.9 to 93.5 cm3. Asdepicted in Fig. 2, the mean CTV of the 10 patients hada shrinkage trend over the five fractions, with the mean of77.4 cm3 from the first fractions and the mean of 65.5 cm3

from the last fractions (r 5�0.911, p 5 0.031). As expected,another observation was that the total dose delivered to pointA increased as the CTV volume increased (r 5 0.785,p 5 0.007, Fig. 3).

CTV coverage and 3D dose comparisons withICRU points

The mean dose to point Awas 28.12 and 29.06 Gy for leftand right side, respectively. For point B, the mean dose was7.49 and 7.66 Gy for left and right side, respectively. Theaverage D90 ranged from 5.44 to 7.15 Gy with 8 of 10 patientsachieving an average D90 of >6.0 Gy. Similarly, 8 of 10

Fig. 2. Mean clinical target volume (CTV) of the 10 patients had

a shrinkage trend over the five fractions, with the mean of 77.4 cm3 from

the first fractions and the mean of 65.5 cm3 from the last fractions

(r 5�0.911, p 5 0.031). Error bars indicate the range of the CTV.

243B. Wang et al. / Brachytherapy 8 (2009) 240e247

patients achieved a V100 of >90%. Table 2 shows the averageV100 (%) and D90 (cGy) over five fractions for CTV. Figures 4and 5 depict the comparison of doses from ICRU referencepoints and doses from 3D plan for bladder and rectum at 2,1, 0.1 cm3, respectively. For bladder, the doses determinedfrom 3D plan correlated significantly from the doses to theICRU reference bladder point, for example, DBV2

(r 5 0.668, p!0.001), DBV1 (r 5 0.666, p!0.001), andDBV0.1 (r 5 0.655, p!0.001); the mean differences betweenthe doses from 3D plan and the ICRU dose were�12, 48, and181 cGy for DBV2, DBV1, and DBV0.1, respectively. However,for rectum, the estimated doses to the ICRU reference rectalpoint did not correlate significantly with the doses deter-mined from 3D plan, for example, DRV2 (r 5 0.251,p 5 0.079), DRV1 (r 5 0.279, p 5 0.049), and DBV0.1

(r 5 0.282, p 5 0.047); the mean differences between thedoses from 3D plan and the ICRU dose were 12, 68, and217 cGy for DRV2, DRV1, and DRV0.1, respectively. The dosedistribution from the bladder ranged greater than that from

Fig. 3. Correlation of total dose at point A with mean clinical target

volume for 10 patients (r 5 0.785, p 5 0.007).

the rectum and we believe it was caused by the bladder filledin more various pattern than the rectum. Figure 6 shows thebladder and rectum volume dose information after normal-ized to the averaged point A dose for 50 implants. The datain this figure include all fractions of 10 patients. It is shownthat the dose for critical organ varied dramatically for eachimplant.

Fig. 4. Comparison of bladder dose calculated at ICRU bladder reference

point and the minimal dose for most irradiated (a) 2 cm3 (DBV2); (b) 1 cm3

(DBV1); (c) 0.1 cm3 (DBV0.1) of bladder from 3D plan.

Fig. 5. Comparison of rectal dose calculated at ICRU rectal reference

point and the minimal dose for most irradiated (a) 2 cm3 (DRV2); (b) 1

cm3 (DRV1); (c) 0.1 cm3 (DRV0.1) of rectum from 3D plan.

Table 2

Average V100 (%) and D90 (cGy) over five fractions for CTV

Subject # 1 2 3 4 5 6 7 8 9 10

Average V100 (%) 83 92 70 91 92 97 92 90 93 96

Average D90 (cGy) 544 647 425 679 629 715 635 614 658 695

Abbreviations: CTV 5 clinical target volume; D90 5 dose received by

at least 90% of volume; V100 5 volume treated with at least prescribed

dose.

Table 3

Ratio of the bladder and rectum dose from 3D plan to ICRU point dose

from several studies compared with this study

Bladder

range

Rectum

range

Bladder

mean

Rectum

mean

Schoeppel et al. (35) 1.4e2.7 0.9e2.1 2.3 1.3

Ling et al. (34) 1.0e4.1 1.4e2.5 2.0 1.9

Pelloski et al. (10) 0.9e3.5 0.8e1.2 1.6 1.0

Kapp et al. (33) 1.0e5.4 1.1e2.7 2.4 1.4

Barillot et al. (32) 0.8e7.1 d 2.7 d

Sun et al. (11) 1.1e2.8 1.1e2.1 1.6 1.5

Kirisits et al., D0.1 cc (8) d d 1.6 1.1

Kirisits et al., D1 cc (8) d d 1.2 1.0

Kirisits et al., D2 cc (8) d d 1.1 0.9

Lindegaard et al., D0.1 cc

(25)

d d 1.3 1.0

Lindegaard et al., D1 cc

(25)

d d 1.1 1.0

Lindegaard et al., D2 cc

(25)

d d 1.1 0.9

Lang et al., D0.1 cc (36) d d 1.7 1.1

Lang et al., D2 cc (36) d d 1.4 1.0

This study, D1 cc 0.7e1.9 0.6e2.0 1.1 1.2

Abbreviations: D0.1 cc, D1 cc, D2 cc 5 minimal dose for most irradiated

0.1, 1, and 2 cm3, respectively.

244 B. Wang et al. / Brachytherapy 8 (2009) 240e247

Discussion

A review of our institution’s experience with CT-basedbrachytherapy in the first 50 implants showed that excellentCTV coverage was achieved. Optimal CTV coverage anddose to point A with consideration of the bladder and rectaldoses are essential factors to achieve optimal treatmentoutcomes and long-term cure of cervical cancer withminimal bladder and rectum toxicities. It has been estab-lished that a higher dose to point A corresponds to

improved local control rates (27, 28). Point A may be aninadequate marker for doseeresponse curves, whereastumor target and high-risk CTV (HR-CTV) may be a bettermarker specifically looking at D90. Muschitz et al. (29)showed that patients with no residual disease at the timeof surgery after brachytherapy were found to have largermean treated volumes and better mean coverage of grosstumor volume (GTV) and CTV when compared to the otherpatients with residual disease at the time of surgery.Because patients with residual disease had larger tumors,tumor size was considered as a poor prognostic factor.However, larger tumor size itself impairs adequate GTVand CTV coverage due to potential toxicity to the criticalorgans like the bladder and rectum (21).

In our study, CTV decreased with subsequent HDR frac-tions as both tumor and normal uterus would naturallydecrease with time and subsequent radiation treatments(Fig. 2). To account for tumor shrinkage during treatment,the Gynecological GEC-ESTRO Working Group (30, 31)proposed the division of CTV into two groups, a HR-CTV and an intermediate-risk CTV (IR-CTV); a HR-CTVto represent all macroscopic disease including the entirecervix and the presumed extracervical tumor extension at

Fig. 6. Bladder (a) and rectum (b) volume dose information after being normalized to the averaged point A dose for 50 fractions of 10 patients. Fractions #1

through #5 correspond to the first through fifth fractions for patient #1, fractions #6 through #10 for patient #2, etc.

245B. Wang et al. / Brachytherapy 8 (2009) 240e247

time of each brachytherapy insertion, and an IR-CTV toinclude all microscopic disease including original grosstumor volume and cervix volume at initial diagnosis. Alower dose of 60 Gy to cover microscopic disease was sug-gested for the IR-CTV, whereas a higher dose of80e90þ Gy was recommended for the HR-CTV to encom-pass all residual macroscopic disease (30, 31).

In this study, the ratio of DBV1 to the ICRU reference pointfor bladder was relatively low, with a mean ratio of 1.1(range, 0.7e1.9). As shown in Table 3, our finding agreeswith more recent studies with 3D planning (8, 25). Weroutinely used CT images to evaluate isodose distributions

and optimized the final plans manually considering boththe CTV coverage and sparing of organs at risk to avoidsignificant high bladder dose. As also shown in Table 3, ourdata for the ratios of DRV1 to ICRU reference point consis-tently correlates with other studies with 3D planning (8, 10,25, 32e35). The mean for this ratio ranges from 0.9 to 1.9for all these studies. The differences among these studieswere due to whether or not gauze containing a radiopaquethread was routinely used to pack the vagina during the ICBTapplicators.

In this study, we found dose to point A increased asCTV increased and we believe this is reasonable

246 B. Wang et al. / Brachytherapy 8 (2009) 240e247

considering our prescription dose was to cover the CTVwith the 100% isodose line. As a result, point A dosewas higher than traditional 2D planning dose whencovering a larger CTV volume. Adequate identificationof GTV and CTV is critical in treatment planning andrequires integration of 3D anatomy with both clinicaland CT findings (18). Utilization of Positron EmissionTomography-CT (PET-CT) or MRI fusion for treatmentplanning should be considered when available. Our studyused both clinical and radiographic information for plan-ning and determination of GTV and CTV; however, PE-TeCT fusion was not available and CTeMRI fusionwas not used with every brachytherapy insertion.Although MRI evaluation aids in delineating cervix tumorfrom normal cervix and uterus, this technology is morecostly, time consuming, and may not be readily availablein the community setting. However, when available,MRIeCT fusion should be used at minimum for the firstHDR treatment.

Target concepts for image-guided brachytherapy arealready available (18, 31), and therefore further studiesshould follow these recommendations for determinationof the adequate target dose, and tolerance doses to normaltissues. In addition, traditional ICRU reference points donot incorporate doses to the sigmoid colon. Although ourpresent study did not analyze dose to the sigmoid colon,the doses to the sigmoid colon should be considered asa part of normal structure during the contouring procedurewith a dose constraint of 70 GyEQD2 (31).

Our study is limited by (1) We did not use Gynecolog-ical GEC-ESTRO Working Group guidelines for HR-CTV, this in part was due to the fact that patients did nothave MRI with applicators in place or MRIeCT fusion toproperly delineate gross tumor volume, which is difficulton CT alone, this in part was due to limitations in resourcesand technology to fuse MRI with CT. (2) Our CTV wasquite large to recreate a more traditional pear-shaped treat-ment volume as we were prescribing to 100% isodose line.(3) We did not outline sigmoid colon and create DVHs. But,we do know that sigmoid toxicity and dose to sigmoid canbe unexpectedly higher than previously thought and shouldbe contoured. (4) We did not look at toxicity or treatmentoutcome to correlate our results to clinical outcome.

Conclusions

CT-based 3D image brachytherapy can provide morequantitative information than the traditional film-based2D planning where only point A was used for dose prescrip-tion. CT-based 3D planning is valuable to evaluate changesin target size, target coverage, dose to point A, and doses tocritical organs. This approach will ensure adequate CTVcoverage if the CTV is extended outside of point A or avoidoverdose to normal tissue if CTV is well within point A.Our experience showed that significant shrinkage of both

gross tumor and normal uterus occurred during the courseof brachytherapy, resulting in a lower point A dose withsuccessive brachytherapy implants, while no clinical dataabout tumor control and side effects were presented.

Acknowledgment

The authors would like to thank Dr. David K. Gaffneyfor his help reviewing the manuscript.

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