Brachytherapy 13 (2014) 562e567

Evaluation of intrafraction motion of the organs at risk in image-based brachytherapy of cervical cancer Vijai Simha1,*, Firuza Darius Patel1, Suresh Chander Sharma1, Bhavana Rai1, Arun Singh Oinam1, Rahul krishnatry2, Bhaswanth Dhanireddy1 1

Department of Radiotherapy and Oncology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India 2 Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, India

ABSTRACT

PURPOSE/INTRODUCTION: To assess the variation in the doses received by the organs at risk (OARs) that can occur during treatment planning of cervical cancer by image-based brachytherapy. METHODS AND MATERIALS: After intracavitary application, two sets of imagesdCT and MRIdwere obtained. The two sets of images were fused together with respect to the applicator. Contouring was done separately on CT and MR images. Dose received by the OARs on CT images with respect to the plans made on the MR images was estimated and compared with those on the MR images. RESULTS: Although there was always a difference between the dose received by the OARs based on the CT and MRI contours, it was not significant for the bladder and rectum; 2 cc doses differed by 0.49 Gy (0.44) p 5 0.28 for the bladder and 0.30 Gy (0.29) p 5 0.16 for the rectum. The 1 cc and 0.1 cc differences were also not significant. However for the sigmoid colon, there was significant intrafraction variation in the 2 cc doses 0.61 (0.6) p 5 0.001, 1 cc doses 0.73 (0.67) Gy p 5 0.00, and 0.1 cc dose 0.97 (0.93) Gy p 5 0.009. CONCLUSIONS: The variation in the doses to the OARs must be considered while weighing target coverage against overdose to the OARs. Although not significant for the bladder and rectum, it was significant for the sigmoid colon. Estimated doses to OARs on the planning system may not be the same dose delivered at the time of treatment. Ó 2014 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Keywords:

Image-based brachytherapy; Organs at risk; Organ motion; Optimization; Intrafraction motion; Intrafraction changes

Introduction Brachytherapy in cervical cancer plays a very important role in obtaining high cure rates with minimum complications. Traditionally, the doses delivered to the organs at risk (OARs) during cervical brachytherapy have been represented by International Commission on Radiation Units and Measurement points (1). It is increasingly being

Received 21 January 2014; received in revised form 1 May 2014; accepted 12 May 2014. Grants: This study did not require any grants. Conflicts of interest: None to report. * Corresponding author. Department of Radiotherapy and Oncology, Post Graduate Institute of Medical Education and Research (PGIMER), Sector 12, Chandigarh 160012, India. Tel.: þ91-991-417-9639. E-mail address: [email protected] (V. Simha).

recognized that the dose to the OARs cannot be represented by points as there is a steep dose gradient because of the proximity to the brachytherapy sources (2, 3). With the introduction of CT, the external contours of the bladder and rectum can be determined with a reasonable accuracy and the organ can be delineated as a single volume (4, 5). Sectional image-based planning enables greater accuracy and reproducibility of topography of the OARs and reliable calculation of the doses received by the OARs (5, 6). CT and MRI provide equal quality for discrimination of the bladder, rectum, and sigmoid (7). Delineation of organ contour permits a reliable estimation of the dose actually delivered to 2 and 1 cc of the wall of the organ exposed to a high dose. The parameters D2cc, D1cc, and D0.1cc (doses received by most exposed part of 2, 1, and 0.1 cc volume, respectively) for bladder, rectum, and sigmoid colon are usually recorded (8). Studies have demonstrated doseeeffect

1538-4721/$ - see front matter Ó 2014 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2014.05.016

V. Simha et al. / Brachytherapy 13 (2014) 562e567

relationship to small volumes of OARs irradiated and have found good correlation between the dose to 2 cc volumes and Grade 2e4 toxicity (9, 10). We would like to qualify the term intrafraction motion. In teletherapy, it would be applicable to the motion occurring during the short time the patient is actually undergoing treatment. However in brachytherapy, it is important to realize that the changes that occur after implantation of the applicator and before and during the treatment also have an impact on the final treatment plan, optimization, and dose distribution, and hence these events are included under the term fraction. Image-based brachytherapy is a long labor intense procedure, and there is a definite possibility that changes in the volume and position of the OARs can occur. These differences in volumes and geometry of the OARs can arise from the differences in the filling and motion of the OARs, the movement of the patient during transfer of the patient from one place to another, or also to a lesser extent from interobserver differences in contouring and OAR movement with respiration (11). The net result from these various motions is that there may be a difference in the doses calculated and the doses actually received by the OARs. The practical way to substantiate this difference is to measure the change in the doses received by small volumes of OARs with respect to the applicator, which will ultimately carry the radioactive source. Despite the ability of the CT scans to quantify the doses received by small volumes of the OARs, the reproducibility of the same doses in the patient during the actual treatment is also critical as nowadays, more and more emphasis is laid on optimization to limit the doses to the OARs (12, 13). If there are significant differences in the doses calculated and doses received, then the whole practice of optimization in image-based brachytherapy may be called into question. Also as the intermediate risk clinical target volume (IRCTV) is limited by the OARs (14), the exact delineation of the IRCTV is dependent on the OAR geometry and may change as it changes with time.

Methods and materials Between November 2010 and January 2013, we treated 50 patients with our in-house image-based brachytherapy protocol, which consisted of a pretreatment MRI, chemoradiation, followed by MR image-based brachytherapy. External radiation was delivered by three-dimensional conformal radiotherapy to the whole pelvis, and a dose of 46 Gy in 23 fractions was delivered over a period of 4 ½ weeks with weekly cisplatin at a dose of 40 mg/m2. Brachytherapy was delivered in four fractions of 7 Gy each. During brachytherapy, applicator was inserted under general anesthesia and immobilized with compact gauze packing of the vagina and a stay suture on the vulva. A T-bandage was also used to secure the applicator to the

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pelvis. An MRI was done for identification of the target volumes. Patients also underwent a CT scan to facilitate the planning process as it helped in applicator reconstruction as our department did not have the library model plans for reconstruction on Oncentra Master Plan version 3.0 software (Nucletron, an Elekta company, Elekta AB, Stockholm, Sweden). There was a time gap of an average of 2 h (1/2e3½ h) between acquisition of MRI and CT and average 7 h (5e8 h) between applicator placement and treatment delivery with the major delay being in acquiring the MRI as it had been done in the radiology department. A bladder-filling protocol was followed before acquisition of the CT and MRI and also before treatment delivery in an attempt to produce uniform bladder filling. Fifty milliliters of normal saline was introduced into the bladder through the Foleys catheter and allowed to drain naturally by gravity. MRI was acquired on Siemens Magnetom 3 T (Siemens AG, Munich, Germany) with sections acquired at 3-mm intervals keeping distance factor zero. CT was acquired on GE LightSpeed CT Scanner (GE Healthcare, Chalfont St. Giles, UK, a unit of General Electric Company) with sections acquired at 2.5 mm thickness. After image acquisition, primary delineation of the target and OAR delineation was done on the MRI. The MR images were fused with the CT images using the manual registration method of Oncentra (Elekta). The applicator geometries in threedimensional MR image were reconstructed manually according to CT image, fused on MR image using the rigid registration of applicator geometry to an accuracy of 1 mm. CTeMRI fusion was done with respect to the applicator geometry only. Contouring was done according to Groupe Europeen de Curietherapie and the European Society for Radiotherapy & Oncology recommendations (14), and the outer wall of the OARs was contoured. Dose of 7 Gy was prescribed to the high-risk clinical target volume (HRCTV). Contouring on both the sets of images was done by only one observer (VS) to eliminate interobserver variations. Plan optimization was done to improve the target coverage or to reduce the doses to the OARs. Patients were treated with a microselectron high-dose rate (Nucletron) unit in the brachytherapy suite. Retrospectively, contouring of the OARs was done on CT scan, and the doses received by the OARs as delineated on the CT was evaluated for the treatment plan used to treat with MRI. Analysis of the difference in the doses of the paired data was done using the Wilcoxon signed rank test.

Results In each of the 50 patients evaluated in this study, some amount of OAR movement always occurred between acquisition of CT and MRI. No contour of any of the OAR was exactly geometrically similar when the MR and CT images were superimposed on each other (Figure 1). The average change in the volume of the bladder between

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Fig. 1. The difference in the position of the organs at risk that can occur in relation to the applicator in the period between the acquisition of CT and MRI. The outer contours of the bladder and rectum show minimal change with respect to the applicator, whereas the sigmoid can show gross changes because of its free mobility.

the CT and MRI was 15.7 (13.8) cc and for the rectum it was 7.8 (6.7) cc (Table 1). Similarly, change in the volume for the sigmoid was 14.9 (13.25) cc. The change in the geometry and volume of the OARs also resulted in the changes of the D2cc, D1cc, and D0.1cc doses. The average change in the 2 cc doses of the bladder between CT and MRI was 0.49 (0.44) Gy, 0.30 (0.29) Gy for the rectum, and 0.61 (0.60) Gy (Table 2) for the sigmoid. Similar variations were noted in the D0.1cc, D1cc, doses as well (Table 2). With respect to our prescribed dose of 7 Gy per fraction, 11 of the 50 patients had a variation in the bladder dose of greater than 10% (0.7 Gy). Variation of greater than 10% of the prescribed dose was seen in 6 patients for the rectum and 18 patients for the sigmoid. To summarize the dosimetric differences, the variations occurred most for the sigmoid followed by the bladder and least for the rectum (Figure 2). In all the patients after superimposing MRI onto the CT, it was seen that the IRCTV contoured on the MR images did not hold good for the CT images because of motion and geometric displacement of the OARs (Figs. 1 and 2).

Discussion In this study, we have attempted to define dosimetric differences because of variations and displacement of the OARs in relation to the applicator. For OARs, the minimum dose in the most irradiated tissue volume is recommended for reporting: 0.1, 1, and 2 cc (8). Doseeeffect relationships for induction of late side effects have been proposed for the OARs (9, 10). For the urinary bladder, D2cc is considered, for which equivalent dose at 2 Gy per fraction (EQD2) of 100 Gy can be used as clinical cutoff for morbidity. For rectal morbidity, D2cc related with Grade 2e4 side effects and a dose of 78 Gy EQD2 resulted in a 10% probability of Grade 2 side effects (10). However for the sigmoid, a low probability of side effects was observed (10), perhaps because of high variability of sigmoid topography between applications. In an observational study by Sturdza et al. (15), of 22 patients, not a single case could be identified in which sigmoid loops were identically positioned in the proximity of the applicator between the fractions. In the absence of definite data regarding the sigmoid toxicity and the observed intrafraction variations observed in the present study, we recommend that dose must not be

Table 1 The average and median volumes of the OARs in MR and CT images, the average changes in the volumes, and the range of variation in the volumes OAR change in volume

Mean (SD) cc

Median (IQR) cc

Minimum change in volume (cc)

Maximum change in volume (cc)

Bladder Rectum Sigmoid

15.7 (13.8) 7.8 (6.7) 14.9 (13.25)

12.27 (12.18) 6.43 (7.85) 9.62 (15)

0.22 0 0.66

61.45 28.72 52.79

OARs 5 organs at risk; SD 5 standard deviation; IQR 5 interquartile range.

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Table 2 The average doses to the 2, 1, and 0.1 cc of the bladder, rectum, and sigmoid and the range of the changes in the dose that can occur between the two sets of images taken on the same day MRI dose OAR dose Bladder (cc dose) 2 1 0.1 Rectum (cc dose) 2 1 0.1 Sigmoid (cc dose) 2 1 0.1

CT dose

Difference in MRI and CT doses

Mean (SD) Gy

Range of difference p-Value

Maximumeminimum Gy

5.52 (1.29) 6.08 (1.37) 7.4 (1.59)

5.65 (1.1) 6.23 (1.19) 7.68 (1.49)

0.49 (0.44) 0.56 (0.55) 0.84 (0.74)

0.28 0.32 0.26

0.01e1.91 0.2e2.47 0.06e4.29

2.72 (1.29) 3.01 (1.37) 3.59 (1.59)

2.88 (0.91) 3.22 (1.04) 3.91 (1.29)

0.30 (0.29) 0.42 (0.59) 0.50 (0.66)

0.16 0.48 0.12

0e1.26 0e3.13 0.1e3.56

4.75 (1.29) 5.35 (1.37) 6.53 (1.59)

4.35 (1.37) 4.86 (1.53) 6.07 (2.2)

0.61 (0.6) 0.73 (0.67) 0.97 (0.93)

0.001 0.000 0.009

0e2.41 0e2.75 0e3.98

SD 5 standard deviation.

compromised to the HRCTV to keep the sigmoid doses within limits. In our study, the doses to the HRCTV and IRCTV was assumed to be the same on the CT and MRI as the applicator was rendered immobile in relation to cervix by use of compact vaginal gauze packing and also by use of a labial stay suture. Though variations were found between the D2cc, D1cc, and D0.1cc for the bladder and rectum, but they were not statistically significant. However, the sigmoid colon has a broad fan-shaped mesentery with a long attachment at its origin allowing for varying degrees of distension and pressure according to its luminal contents. This extreme mobility conferred on the sigmoid colon may even result in a volvulus of that bowel (16). In our study, as a result of the mobility of the sigmoid, there

was a significant difference in the dose to the 2, 1, and 0.1 cc of the sigmoid between CT and MR imaging. Although the 2 cc doses showed an average change of nearly 10% of the prescribed dose, the variation in the 1 and 0.1 cc doses was much higher than 10%. Although statistically we have shown that there is not much dosimetric intrafraction variation for the bladder and rectum, large differences in the D2cc doses have occurred in individual patients in this study. Change in D2cc dose as high as 1.91 Gy (27.2% change with respect to prescribed dose) for the bladder 1.26 Gy (18% change with respect to prescribed dose) for the rectum and 2.41 Gy (34.4% change with respect to prescribed dose) for the sigmoid have been seen. In a similar study by Anderson et al. (17), a

Fig. 2. A fused sagittal view of CT and MRI with respect to the applicator. The posterior wall of the bladder and the anterior wall of the rectum maintain a similar relation to the applicator. However, the sigmoid colon shows significant change in position owing to its free mobility.

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pretreatment MRI was taken after an average of 4.75 h of planning MRI in 21 patients, and it was seen that although the mean changes in the dose to the OARs was not significant, significant changes in individual patients did occur. Also the time elapsed between the two MRI scans in that study did not correlate with the change in the OAR doses. Our study differs from the study by Anderson in that the variations in the doses to the sigmoid were significant. It must be further noted that this variation depicted in our study is only for a single fraction and if similar variation is produced in multiple fractions (our protocol administers four fractions of 7 Gy at brachytherapy); the final effect on the uncertainty of the EQD2 dose received by the OARs is likely to get further magnified. Whenever a plan is optimized so as to decrease the dose to the OARs, it always means constricting of the isodose curves around the applicator and a fall in the HRCTV and Point A dose. Dramatically optimizing standard treatment plans so as to decrease the dose to the OAR is not justified as we have shown here that there may be a significant change in the dose between two sets of images taken on the same day. Also it is well accepted that a poorly optimized plan is worse than a standard plan where the prescribed dose is normalized to Point A. Also as inferred from this study, the geometry and volume of IRCTV (as defined by Groupe Europeen de Curietherapie and the European Society for Radiotherapy & Oncology) (8) is likely to change as the geometry of OARs changes with time. Thus, the IRCTV is best regarded as a conceptual rather than an actual entity, and the margins given around the HRCTV to contour the IRCTV should not be limited by the OARs as the topography of the OARs is likely to change over a period, and sometimes the OARs may well lie adjacent to the HRCTV. The limitations of this study are that the variations in the OAR doses have been evaluated only between CT and MR imaging and not between planning and treatment delivery. Although it would be advisable to keep the time between planning and treatment to the minimum, it must be pointed out that the changes can occur to increase and decrease the variation onto the next day as seen in a study by Lang et al. (18). While estimating the total dose to an OAR as EQD2, it has always been assumed in the past that the same area of the OAR is in the high-dose region, although this may not be true as there is organ motion and deformation between the fractions and also within a fraction as seen in this study. Also it is possible that applicator displacement (if inadequately secured) can occur between image acquisition and treatment. This adds another element of uncertainty in the practice of image-based brachytherapy.

Summary This study quantifies the volume changes that occur in the OARs and the resultant changes in the doses to small

volumes of the OAR that can occur because of volume and position changes. Despite intrafractional variations, our results encourage the practice of cautious optimization in image-based brachytherapy considering the fact that dose calculated may not be the exact dose that is received by the OARs but is likely to be very close as far as the bladder and rectum are concerned. For the sigmoid colon, this study has shown that there is likely to be significant differences in the dose received over a period as it is freely mobile within the pelvis. Hence, overenthusiastic optimization to decrease the dose to the sigmoid colon is not encouraged. Also occasionally, dramatic variation of the doses can occur for the bladder and rectum on an individual basis, the clinician must thoroughly justify the consequent fall in the dose to HRCTV that can occur because of optimization. The variation in the topography of the OARs may explain some of the unexplained toxicities that do not correlate with the doses delivered. Hence, it is important to realize that planned dose to the OAR is not necessarily the dose received by these organs at the time of treatment delivery.

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Evaluation of intrafraction motion of the organs at risk in image-based brachytherapy of cervical cancer.

To assess the variation in the doses received by the organs at risk (OARs) that can occur during treatment planning of cervical cancer by image-based ...
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