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Comparison of dosimetric parameters derived from whole organ and wall contours for bladder and rectum in cervical cancer patients treated with intracavitary and interstitial brachytherapy
Radiotherapy and Oncology xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Comparison of dosimetric parameters derived from whole organ and wall contours for bladder and rectum in cervical cancer patients treated with intracavitary and interstitial brachytherapy Rachel Gerber a,b,1, Alexandra Rink a,b,1, Jennifer Croke a,b, Jette Borg a,b, Akbar Beiki-Ardakani a, Anthony Fyles a,b, Michael Milosevic a,b, Jason Xie a, Harald Keller a,b, Kathy Han a,b,⇑ a
Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto; and b Department of Radiation Oncology, University of Toronto, Canada
a r t i c l e
i n f o
Article history: Received 13 August 2017 Received in revised form 18 December 2017 Accepted 23 January 2018 Available online xxxx
a b s t r a c t For volumes up to 2 cm3 of the bladder and possibly up to 5 cm3 of the rectum, doses computed from the whole organ were good estimates of the doses in the wall in cervix brachytherapy, and there were no significant differences between patients treated with or without interstitial needles. Ó 2018 Elsevier B.V. All rights reserved. Radiotherapy and Oncology xxx (2018) xxx–xxx
Keywords: Interstitial brachytherapy Cervical cancer Bladder Rectum Dosimetric parameters Organ delineation
Patients with locally advanced cervical cancer are generally treated with external beam radiotherapy (EBRT), concurrent cisplatin chemotherapy and brachytherapy as a standard of care. Brachytherapy escalates the dose to the primary tumor while minimizing the dose to surrounding organs at risk (OARs). The use of brachytherapy in patients with cervical cancer has been associated with better local control and survival [1,2]. Furthermore, 3D brachytherapy with magnetic resonance imaging (MRI)-guidance and interstitial needles further improves local control while reducing severe morbidity [3–8]. Previous studies have established dose–effect relationships between the minimum dose delivered to the most irradiated 0.1–2 cm3 (D0.1 D2cm3) of rectum and bladder and the incidence of late gastrointestinal and genitourinary morbidities [5,9,10], respectively. For practical reasons, whole organ (external contour) delineation is more widely performed than organ wall delineation. A previous study on 15 cervix patients treated with ring and tandem applicators showed that D2cm3 for whole bladder and rectum, computed from external contours, provided a good estimate of D2cm3 for the organ wall. However, this was not the case for
⇑ Corresponding author at: Department of Radiation Oncology, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. E-mail address: [email protected] (K. Han). 1 Contributed equally.
D5cm3 or D10cm3 [11]. Therefore, the Gynaecological (GYN) Groupe Européen de Curiethérapie–European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) and International Commission on Radiation Units Report 89 (ICRU89) recommend delineating the organ wall if larger organ-wall volumes (>2–3 cm3) needed to be reported [12,13]. Kim et al. found that although D1cm3, D2cm3, D5cm3 and D15cm3 were associated with rectosigmoid mucosal changes on rectosigmoidoscopy and late complications on univariable analysis, only D5cm3 remained predictive on multivariable analysis [14]. While intermediate doses might be relevant for toxicity [13,15], D5cm3 or D10cm3 has not been widely studied potentially due to the issue of whole organ and organ wall delineation. Given the potential importance of intermediate doses and the increasing use of interstitial needles in combination with intracavitary treatment with higher conformality, this study compared dosimetric parameters for whole organ to organ wall for bladder and rectum in patients treated with ring and tandem with or without interstitial needles to assess whether GEC-ESTRO recommendations were applicable in patients treated with interstitial needles. We hypothesized that the higher conformality and lower OAR doses achieved with interstitial needles would result in smaller dose gradients across OARs (especially for emptier OARs which are usually further away from hyperdose regions), and therefore smaller differences between whole organ and organ wall doses.
https://doi.org/10.1016/j.radonc.2018.01.015 0167-8140/Ó 2018 Elsevier B.V. All rights reserved.
Please cite this article in press as: Gerber R et al. Comparison of dosimetric parameters derived from whole organ and wall contours for bladder and rectum in cervical cancer patients treated with intracavitary and interstitial brachytherapy. Radiother Oncol (2018), https://doi.org/10.1016/j.radonc.2018.01.015
2
OAR delineation in cervix brachytherapy
Materials and methods Patients Sixty-two women with FIGO stage IB–IIIB cervical cancer treated with definitive EBRT, cisplatin, and MRI-guided high-dose rate (HDR) brachytherapy between 2014 and 2016 using the interstitial ring CT-MR applicator with or without parallel interstitial needles (Elekta AB, Stockholm, Sweden) were included. Two applicator insertions (with interstitial needles usually at least at 3 and 9 o’clock positions when used) were performed under general anesthesia approximately 1 week apart; two fractions with a planning aim of 7 Gy for D90% of the CTVHR were administered per insertion approximately 20 h apart. Patients were routinely given an enema the night before applicator insertion to empty the rectum. The majority of patients were treated with empty bladder during brachytherapy; 12 patients were treated with full bladder for fraction 1 to displace the small bowel and thereby decrease the bowel dose received.
39 ± 13 cm3 and 27 ± 7 cm3, respectively. Bladder whole organ and wall volumes were 97 ± 63 cm3 and 33 ± 8 cm3, respectively. The mean rectum wall D2cm3 was 3.3 ± 1.0 Gy per fraction and 61 ± 6 Gy3 (EQD2); the mean bladder wall D2cm3 was 4.8 ± 1.1 Gy per fraction and 75 ± 10 Gy3 (EQD2). As the volumes for whole organ and organ wall increase, the dose–volume histogram (DVH) lines diverge (Fig. 1). Table E1 lists the ratios of doses computed for the whole organ to that for the wall for all fractions and EQD2. The mean ratios for bladder D0.1 D2cm3, and rectum D0.1 D10cm3 were all 1.2, except for fraction 2 rectum D10cm3 (1.3). The mean ratios for bladder D5 D10cm3 were larger. The mean absolute differences between doses to whole organ and organ wall for bladder D0.1 D2cm3 and rectum D0.1 D10cm3 were all 0.4 Gy, except for fraction 2 rectum D5 D10cm3 (0.6–0.8 Gy, Table E1). Larger absolute differences for bladder D5 D10cm3 were observed. The mean absolute differences between EQD2 doses to whole organ and organ wall were 0.9 Gy3 for rectum D2cm3, 2.3 Gy3 for rectum D10cm3, and 3.0 Gy3 for bladder D2cm3.
Treatment planning Bladder Volume (cm3)
(A) 100 80 60 Whole organ
40
Organ wall
20 0 0
0.5
1
1.5
Relave dose 35 Rectum Volume (cm3)
Axial, sagittal and coronal fast spin echo T2-weighted MR images were obtained using a 3 Tesla MAGNETOM Verio prior to each fraction (Siemens Medical Systems, Erlangen, DE) (TE/TR 102/4500 ms, slice/gap thickness 3/0 mm, matrix 320 256, FOV 20 cm). An 8-channel torso phased-array coil was used for all scans. High-risk clinical target volume (CTVHR) was contoured as per GEC-ESTRO recommendations [16]. The whole organ and wall of the bladder and rectum were delineated as per Wachter-Gerstner et al. [11]. Brachytherapy plans were manually optimized in Oncentra Brachy (v4.3 or 4.5, Elekta) using the library plan as a starting point and the following planning aims up to early 2016: minimum combined EBRT and brachytherapy equivalent 2 Gy dose (EQD2) to 90% of the CTVHR (CTVHR D90%) of 85 Gy10 (a/b = 10); and maximum D2cm3 to bladder, rectum and sigmoid of 90 Gy3 (a/b = 3), 75 Gy3 and 75 Gy3, respectively. Planning aims from the EMBRACE II study protocol were adopted in 2016: 90–95 Gy10, 80 Gy3, 65 Gy3 and 70 Gy3, respectively. On average, 27% ± standard deviation (SD) 14% of the total dose came from needles. The minimum absolute brachytherapy dose delivered to most irradiated 0.1 cm3, 1 cm3, 2 cm3, 5 cm3 and 10 cm3 of the whole organ and wall of bladder and rectum were computed for all fractions. The impact of interstitial needles and OAR volume were explored.
30 25 20 15
Whole organ
10
Organ wall
5 0 0
0.5
1
Relave dose
Statistical analysis
(B)
The ratio of whole organ to wall dose and the absolute difference were determined for each dosimetric parameter. The ratios and absolute differences for those treated (a) with or without interstitial needles, and (b) with full vs. empty bladder were compared using the Wilcoxon rank sum test. The correlation between rectum or bladder volume with whole organ to wall dose ratios were evaluated by Spearman’s correlation coefficient. Since 10 parameters (ratios and absolute differences) were tested per organ, the a-level for rejecting the null hypothesis of no difference/correlation was set at 0.005 (Bonferroni’s correction). Results Of the 62 patients included in this study, 79% of patients had squamous cell carcinoma and 50% of patients had FIGO stage IIB–IIIB disease. The mean CTVHR was 31 ± 14 cm3 (SD); the combined EBRT and brachytherapy mean CTVHR D90% was 93 ± 4 Gy10. Rectum whole organ and wall volumes for fraction 1 were
Fig. 1. Example of a patient’s (A) dose–volume histograms for the bladder and rectum whole organ versus wall (where x-axis was normalized to the prescription dose of 7 Gy); and (B) corresponding dose distribution (red shaded contour = CTVHR; blue isodose line = 3.5 Gy, beige isodose line = 4.4 Gy, red isodose line = 7 Gy; and white isodose line = 14 Gy). The dose to 2 cm3 of the bladder and rectum whole organ contour is good estimate of dose to the respective wall. As the volume increases, the difference between the dose to the whole organ vs. wall increases, especially for reporting volumes > 10 cm3.
Please cite this article in press as: Gerber R et al. Comparison of dosimetric parameters derived from whole organ and wall contours for bladder and rectum in cervical cancer patients treated with intracavitary and interstitial brachytherapy. Radiother Oncol (2018), https://doi.org/10.1016/j.radonc.2018.01.015
3
R. Gerber et al. / Radiotherapy and Oncology xxx (2018) xxx–xxx Table 1 Dosimetric parameters for fraction 1 for, intracavitary technique, intracavitary/interstitial technique, bladder full and bladder empty. Dosimetric parameter (mean ± SD)
Intracavitary (n = 30)
Intracavitary/interstitial (n = 32)
Bladder full (n = 12)
Bladder empty (n = 50)
Rectum Ratio of organ to wall dose (–) D0.1cm3 D1cm3 D2cm3 D5cm3 D10cm3
1.0 ± 0.004 1.0 ± 0.01 1.0 ± 0.03 1.1 ± 0.1 1.2 ± 0.1
1.0 ± 0.004 1.0 ± 0.03 1.0 ± 0.1 1.1 ± 0.1 1.2 ± 0.1
1.0 ± 0.002 1.0 ± 0.003 1.0 ± 0.01 1.1 ± 0.04 1.2 ± 0.1
1.0 ± 0.004 1.0 ± 0.02 1.0 ± 0.1 1.1 ± 0.1 1.2 ± 0.1
Absolute difference between organ and wall dose (Gy) 0.01 ± 0.02 D0.1cm3 D1cm3 0.02 ± 0.04 D2cm3 0.1 ± 0.1 0.2 ± 0.1 D5cm3 D10cm3 0.3 ± 0.2
0.01 ± 0.02 0.04 ± 0.1 0.1 ± 0.2 0.2 ± 0.2 0.3 ± 0.2
0.01 ± 0.01 0.01 ± 0.01 0.1 ± 0.1 0.2 ± 0.1 0.3 ± 0.1
0.01 ± 0.03 0.04 ± 0.1 0.1 ± 0.2 0.2 ± 0.2 0.4 ± 0.2
Bladder Ratio of organ to wall dose (–) D0.1cm3 D1cm3 D2cm3 D5cm3 D10cm3
1.0 ± 0.01 1.0 ± 0.03 1.1 ± 0.1 1.3 ± 0.3 1.7 ± 0.6
1.0 ± 0.01 1.0 ± 0.1 1.1 ± 0.1 1.5 ± 0.3* 2.3 ± 0.6*
1.0 ± 0.01 1.0 ± 0.03 1.0 ± 0.1 1.2 ± 0.2* 1.5 ± 0.4*
0.01 ± 0.1 0.1 ± 0.2 0.3 ± 0.4 0.8 ± 0.6 1.2 ± 0.6
0.01 ± 0.1 0.3 ± 0.3 0.6 ± 0.5 1.4 ± 0.6* 2.1 ± 0.4*
0.02 ± 0.1 0.1 ± 0.2 0.2 ± 0.3 0.6 ± 0.5* 0.9 ± 0.5*
1.0 ± 0.01 1.0 ± 0.04 1.1 ± 0.1 1.2 ± 0.2 1.6 ± 0.5
Absolute difference between organ and wall dose (Gy) D0.1cm3 0.01 ± 0.03 D1cm3 0.1 ± 0.3 D2cm3 0.3 ± 0.4 D5cm3 0.7 ± 0.6 D10cm3 1.1 ± 0.7
Abbreviations: D = minimum dose received by the specified volume of rectum or bladder. * p < 0.005 for bladder full vs. empty based on Wilcoxon’s test and Bonferroni’s correction.
Intracavitary compared to combined intracavitary and interstitial brachytherapy For the first application, 30 patients (48%) were treated with ring and tandem only and 32 patients (52%) were treated with ring, tandem, and interstitial needles. There were no significant differences in any of the bladder or rectum whole organ to wall dose ratios, nor absolute differences, between those treated with or without interstitial technique (Table 1). Subgroup analysis of 9 patients who had intracavitary brachytherapy for the first application but combined intracavitary/interstitial technique for the second application revealed similar ratios and absolute differences between two fractions (statistical testing not performed given the limited number of patients) (Table E2). Correlation with rectum or bladder whole organ volume Analysis of fraction 1 data for all 62 patients showed a weak positive correlation between the rectum whole organ volume and the ratio of whole organ to wall dose for D2cm3 and D10cm3 (r = 0.36, p = 0.004; and r = 0.38, p = 0.002, respectively). For bladder, analysis of fraction 1 data for all 62 patients showed a moderate positive correlation between whole organ volume and the ratios of whole organ to wall dose for D2cm3, D5cm3, and D10cm3 (r = 0.46, p = 0.002; r = 0.50, p < 0.001; and r = 0.65, p < 0.001, respectively). Bladder full compared to bladder empty The impact of a full bladder (12 patients) on the ratios and absolute differences was investigated. The ratios of whole organ to wall doses for bladder D5cm3 and D10cm3 were significantly higher for those treated with full than empty bladder (p < 0.005, Table 1). Similarly, the absolute differences between dose to whole organ and wall only for bladder D5cm3 and D10cm3 are also significantly higher for those treated with full bladder (mean D5cm3 absolute
difference 1.4 vs. 0.6 Gy, and D10cm3 2.1 vs. 0.9 Gy, respectively; p < 0.005, Table 1). The highest ratios and absolute differences (outliers) for D5cm3 and D10cm3 were observed in patients with bladder whole organ volume > 100 cm3. Discussion This study compared dosimetric parameters calculated from whole organ and wall contours for bladder and rectum in patients treated with ring and tandem with or without interstitial needles. There were no significant differences between those treated with or without interstitial needles. Our results for bladder and rectum D2cm3 are consistent with that from Wachter-Gerstner and Olszewska et al., who concluded that doses to the whole organ can be used instead of the wall for volumes < 5 cm3 in cervix patients treated with intracavitary brachytherapy [11,17]. However, our mean whole organ to wall dose ratios and standard deviations for the rectum appear lower than that in the Wachter-Gerstner study, where the mean D2cm3 ratio is 1.2 ± 0.1, D5cm3 1.6 ± 0.3, and D10cm3 2.1 ± 0.6 [11]. The larger volume of rectum in the Wachter-Gerstner study compared to ours (mean 58 ± 22 cm3 vs. 39 ± 13 cm3 for fraction 1, respectively) may explain the differences in the ratios between the studies, since we observe a weak positive correlation between the rectum volume and ratios. Given that the ratio of whole organ to wall dose for D5cm3 rectum (and some D10cm3 rectum) is 1.2 in our study (same as that for D2cm3 in the Wachter-Gerstner study), whole organ doses may potentially be good estimates of wall doses for up to 5 cm3 of the rectum if the rectum is not distended. This result may only apply to practices where only one HDR fraction is delivered per applicator insertion with bowel preparation before the procedure, and may not apply if the second HDR fraction is delivered the day after applicator insertion, with the patient immobilized and thereby higher likelihood of flatus and/or stool causing rectal distension. If our whole organ to wall dose ratio for D5cm3
Please cite this article in press as: Gerber R et al. Comparison of dosimetric parameters derived from whole organ and wall contours for bladder and rectum in cervical cancer patients treated with intracavitary and interstitial brachytherapy. Radiother Oncol (2018), https://doi.org/10.1016/j.radonc.2018.01.015
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OAR delineation in cervix brachytherapy
rectum (the most relevant parameter for predicting toxicity as per Kim et al. [14]) is validated by another study, D5cm3 can be more readily extracted from the whole organ contour and correlated with late toxicity. The uncertainties associated with whole organ versus organ wall contouring observed in our study are similar to that reported by Lang et al. when applying 2 HDR fractions for each applicator insertion compared to individual adaptive planning for each fraction [18], and smaller than that reported by Nesvacil et al. when analyzing inter-/intrafractional anatomical variations [19]. Since whole organ delineation is reliable and quicker than wall delineation, for practical reasons it is the recommended method by the GEC-ESTRO and ICRU89 for small volumes up to 2–3 cm3 [12,13]. We did not find significant differences in any of the bladder or rectum whole organ to wall dose ratios, nor absolute differences, between those treated with or without interstitial brachytherapy. This supports delineating the whole organ for cases treated with combined intracavitary/interstitial technique. As expected, the whole organ to wall dose ratios for bladder D5cm3 and D10cm3 are significantly higher for those treated with full bladder compared to empty bladder (p < 0.005). Bladder filling distends the bladder wall and increases the bladder volume, which results in the minimum dose of the wall for a large volume to be further away from the applicator/high-dose region and hence the larger whole organ to wall dose ratio. Therefore, wall contours should be used for planning, especially when the bladder is full. In conclusion, doses computed for whole organ from the external contour are good estimates of the doses in the wall for 2 cm3 of the bladder and rectum, and possibly for volumes up to 5 cm3 of the rectum if the rectum is not distended. There are no significant differences between those treated with or without interstitial needles in our study. This supports the practice of delineating the whole organ of rectum and bladder in patients treated with combined intracavitary/interstitial brachytherapy for D2cm3. Conflict of interest statement None. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.radonc.2018.01. 015. References [1] Han K, Milosevic M, Fyles A, Pintilie M, Viswanathan AN. Trends in the utilization of brachytherapy in cervical cancer in the United States. Int J Radiat Oncol Biol Phys 2013;87:111–9. [2] Lanciano RM, Martz K, Coia LR, Hanks GE. Tumor and treatment factors improving outcome in stage III-B cervix cancer. Int J Radiat Oncol Biol Phys 1991;20:95–100.
[3] Potter R, Georg P, Dimopoulos JC, et al. Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer. Radiother Oncol 2011;100:116–23. [4] Fokdal L, Sturdza A, Mazeron R, et al. Image guided adaptive brachytherapy with combined intracavitary and interstitial technique improves the therapeutic ratio in locally advanced cervical cancer: analysis from the retroEMBRACE study. Radiother Oncol 2016;120:434–40. [5] Mazeron R, Fokdal LU, Kirchheiner K, et al. Dose–volume effect relationships for late rectal morbidity in patients treated with chemoradiation and MRIguided adaptive brachytherapy for locally advanced cervical cancer: results from the prospective multicenter EMBRACE study. Radiother Oncol 2016;120:412–9. [6] Sturdza A, Potter R, Fokdal LU, et al. Image guided brachytherapy in locally advanced cervical cancer: improved pelvic control and survival in RetroEMBRACE, a multicenter cohort study. Radiother Oncol 2016;120:428–33. [7] Lindegaard JC, Fokdal LU, Nielsen SK, Juul-Christensen J, Tanderup K. MRIguided adaptive radiotherapy in locally advanced cervical cancer from a Nordic perspective. Acta Oncol 2013;52:1510–9. [8] Levitchi M, Charra-Brunaud C, Quetin P, et al. Impact of dosimetric and clinical parameters on clinical side effects in cervix cancer patients treated with 3D pulse-dose-rate intracavitary brachytherapy. Radiother Oncol 2012;103:314–21. [9] Mazeron R, Maroun P, Castelnau-Marchand P, et al. Pulsed-dose rate imageguided adaptive brachytherapy in cervical cancer: dose–volume effect relationships for the rectum and bladder. Radiother Oncol 2015;116:226–32. [10] Georg P, Potter R, Georg D, et al. Dose effect relationship for late side effects of the rectum and urinary bladder in magnetic resonance image-guided adaptive cervix cancer brachytherapy. Int J Radiat Oncol Biol Phys 2012;82:653–7. [11] Wachter-Gerstner N, Wachter S, Reinstadler E, et al. Bladder and rectum dose defined from MRI based treatment planning for cervix cancer brachytherapy: comparison of dose–volume histograms for organ contours and organ wall, comparison with ICRU rectum and bladder reference point. Radiother Oncol 2003;68:269–76. [12] Potter R, Haie-Meder C, Van Limbergen E, et al. Recommendations from gynaecological (GYN) GEC ESTRO working group (II): concepts and terms in 3D image-based treatment planning in cervix cancer brachytherapy-3D dose volume parameters and aspects of 3D image-based anatomy, radiation physics, radiobiology. Radiother Oncol 2006;78:67–77. [13] International Commission of Radiation Units and Measurements. ICRU report 89: prescribing, recording, and reporting brachytherapy for cancer of the cervix. J. ICRU 2013:13. [14] Kim TH, Kim JY, Sohn DK, et al. A prospective observational study with dose volume parameters predicting rectosigmoidoscopic findings and late rectosigmoid bleeding in patients with uterine cervical cancer treatment by definitive radiotherapy. Radiat Oncol 2013;8:28. [15] Ujaimi R, Milosevic M, Fyles A, et al. Intermediate dose–volume parameters and the development of late rectal toxicity after MRI-guided brachytherapy for locally advanced cervix cancer. Brachytherapy 2017. [16] Haie-Meder C, Potter R, Van Limbergen E, et al. Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group (I): concepts and terms in 3D image based 3D treatment planning in cervix cancer brachytherapy with emphasis on MRI assessment of GTV and CTV. Radiother Oncol 2005;74:235–45. [17] Olszewska AM, Saarnack AE, De Boer RW, Van Bunningen BNFM, Steggerda MJ. Comparison of dose–volume histograms and dose-wall histograms of the rectum of patients treated with intracavitary brachytherapy. Radiother Oncol 2001;61:83–5. [18] Lang S, Nesvacil N, Kirisits C, et al. Uncertainty analysis for 3D image-based cervix cancer brachytherapy by repetitive MR imaging: assessment of DVHvariations between two HDR fractions within one applicator insertion and their clinical relevance. Radiother Oncol 2013;107:26–31. [19] Nesvacil N, Tanderup K, Hellebust TP, et al. A multicentre comparison of the dosimetric impact of inter- and intra-fractional anatomical variations in fractionated cervix cancer brachytherapy. Radiother Oncol 2013;107:20–5.
Please cite this article in press as: Gerber R et al. Comparison of dosimetric parameters derived from whole organ and wall contours for bladder and rectum in cervical cancer patients treated with intracavitary and interstitial brachytherapy. Radiother Oncol (2018), https://doi.org/10.1016/j.radonc.2018.01.015
Contents lists available at ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Comparison of dosimetric parameters derived from whole organ and wall contours for bladder and rectum in cervical cancer patients treated with intracavitary and interstitial brachytherapy Rachel Gerber a,b,1, Alexandra Rink a,b,1, Jennifer Croke a,b, Jette Borg a,b, Akbar Beiki-Ardakani a, Anthony Fyles a,b, Michael Milosevic a,b, Jason Xie a, Harald Keller a,b, Kathy Han a,b,⇑ a
Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto; and b Department of Radiation Oncology, University of Toronto, Canada
a r t i c l e
i n f o
Article history: Received 13 August 2017 Received in revised form 18 December 2017 Accepted 23 January 2018 Available online xxxx
a b s t r a c t For volumes up to 2 cm3 of the bladder and possibly up to 5 cm3 of the rectum, doses computed from the whole organ were good estimates of the doses in the wall in cervix brachytherapy, and there were no significant differences between patients treated with or without interstitial needles. Ó 2018 Elsevier B.V. All rights reserved. Radiotherapy and Oncology xxx (2018) xxx–xxx
Keywords: Interstitial brachytherapy Cervical cancer Bladder Rectum Dosimetric parameters Organ delineation
Patients with locally advanced cervical cancer are generally treated with external beam radiotherapy (EBRT), concurrent cisplatin chemotherapy and brachytherapy as a standard of care. Brachytherapy escalates the dose to the primary tumor while minimizing the dose to surrounding organs at risk (OARs). The use of brachytherapy in patients with cervical cancer has been associated with better local control and survival [1,2]. Furthermore, 3D brachytherapy with magnetic resonance imaging (MRI)-guidance and interstitial needles further improves local control while reducing severe morbidity [3–8]. Previous studies have established dose–effect relationships between the minimum dose delivered to the most irradiated 0.1–2 cm3 (D0.1 D2cm3) of rectum and bladder and the incidence of late gastrointestinal and genitourinary morbidities [5,9,10], respectively. For practical reasons, whole organ (external contour) delineation is more widely performed than organ wall delineation. A previous study on 15 cervix patients treated with ring and tandem applicators showed that D2cm3 for whole bladder and rectum, computed from external contours, provided a good estimate of D2cm3 for the organ wall. However, this was not the case for
⇑ Corresponding author at: Department of Radiation Oncology, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. E-mail address: [email protected] (K. Han). 1 Contributed equally.
D5cm3 or D10cm3 [11]. Therefore, the Gynaecological (GYN) Groupe Européen de Curiethérapie–European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) and International Commission on Radiation Units Report 89 (ICRU89) recommend delineating the organ wall if larger organ-wall volumes (>2–3 cm3) needed to be reported [12,13]. Kim et al. found that although D1cm3, D2cm3, D5cm3 and D15cm3 were associated with rectosigmoid mucosal changes on rectosigmoidoscopy and late complications on univariable analysis, only D5cm3 remained predictive on multivariable analysis [14]. While intermediate doses might be relevant for toxicity [13,15], D5cm3 or D10cm3 has not been widely studied potentially due to the issue of whole organ and organ wall delineation. Given the potential importance of intermediate doses and the increasing use of interstitial needles in combination with intracavitary treatment with higher conformality, this study compared dosimetric parameters for whole organ to organ wall for bladder and rectum in patients treated with ring and tandem with or without interstitial needles to assess whether GEC-ESTRO recommendations were applicable in patients treated with interstitial needles. We hypothesized that the higher conformality and lower OAR doses achieved with interstitial needles would result in smaller dose gradients across OARs (especially for emptier OARs which are usually further away from hyperdose regions), and therefore smaller differences between whole organ and organ wall doses.
https://doi.org/10.1016/j.radonc.2018.01.015 0167-8140/Ó 2018 Elsevier B.V. All rights reserved.
Please cite this article in press as: Gerber R et al. Comparison of dosimetric parameters derived from whole organ and wall contours for bladder and rectum in cervical cancer patients treated with intracavitary and interstitial brachytherapy. Radiother Oncol (2018), https://doi.org/10.1016/j.radonc.2018.01.015
2
OAR delineation in cervix brachytherapy
Materials and methods Patients Sixty-two women with FIGO stage IB–IIIB cervical cancer treated with definitive EBRT, cisplatin, and MRI-guided high-dose rate (HDR) brachytherapy between 2014 and 2016 using the interstitial ring CT-MR applicator with or without parallel interstitial needles (Elekta AB, Stockholm, Sweden) were included. Two applicator insertions (with interstitial needles usually at least at 3 and 9 o’clock positions when used) were performed under general anesthesia approximately 1 week apart; two fractions with a planning aim of 7 Gy for D90% of the CTVHR were administered per insertion approximately 20 h apart. Patients were routinely given an enema the night before applicator insertion to empty the rectum. The majority of patients were treated with empty bladder during brachytherapy; 12 patients were treated with full bladder for fraction 1 to displace the small bowel and thereby decrease the bowel dose received.
39 ± 13 cm3 and 27 ± 7 cm3, respectively. Bladder whole organ and wall volumes were 97 ± 63 cm3 and 33 ± 8 cm3, respectively. The mean rectum wall D2cm3 was 3.3 ± 1.0 Gy per fraction and 61 ± 6 Gy3 (EQD2); the mean bladder wall D2cm3 was 4.8 ± 1.1 Gy per fraction and 75 ± 10 Gy3 (EQD2). As the volumes for whole organ and organ wall increase, the dose–volume histogram (DVH) lines diverge (Fig. 1). Table E1 lists the ratios of doses computed for the whole organ to that for the wall for all fractions and EQD2. The mean ratios for bladder D0.1 D2cm3, and rectum D0.1 D10cm3 were all 1.2, except for fraction 2 rectum D10cm3 (1.3). The mean ratios for bladder D5 D10cm3 were larger. The mean absolute differences between doses to whole organ and organ wall for bladder D0.1 D2cm3 and rectum D0.1 D10cm3 were all 0.4 Gy, except for fraction 2 rectum D5 D10cm3 (0.6–0.8 Gy, Table E1). Larger absolute differences for bladder D5 D10cm3 were observed. The mean absolute differences between EQD2 doses to whole organ and organ wall were 0.9 Gy3 for rectum D2cm3, 2.3 Gy3 for rectum D10cm3, and 3.0 Gy3 for bladder D2cm3.
Treatment planning Bladder Volume (cm3)
(A) 100 80 60 Whole organ
40
Organ wall
20 0 0
0.5
1
1.5
Relave dose 35 Rectum Volume (cm3)
Axial, sagittal and coronal fast spin echo T2-weighted MR images were obtained using a 3 Tesla MAGNETOM Verio prior to each fraction (Siemens Medical Systems, Erlangen, DE) (TE/TR 102/4500 ms, slice/gap thickness 3/0 mm, matrix 320 256, FOV 20 cm). An 8-channel torso phased-array coil was used for all scans. High-risk clinical target volume (CTVHR) was contoured as per GEC-ESTRO recommendations [16]. The whole organ and wall of the bladder and rectum were delineated as per Wachter-Gerstner et al. [11]. Brachytherapy plans were manually optimized in Oncentra Brachy (v4.3 or 4.5, Elekta) using the library plan as a starting point and the following planning aims up to early 2016: minimum combined EBRT and brachytherapy equivalent 2 Gy dose (EQD2) to 90% of the CTVHR (CTVHR D90%) of 85 Gy10 (a/b = 10); and maximum D2cm3 to bladder, rectum and sigmoid of 90 Gy3 (a/b = 3), 75 Gy3 and 75 Gy3, respectively. Planning aims from the EMBRACE II study protocol were adopted in 2016: 90–95 Gy10, 80 Gy3, 65 Gy3 and 70 Gy3, respectively. On average, 27% ± standard deviation (SD) 14% of the total dose came from needles. The minimum absolute brachytherapy dose delivered to most irradiated 0.1 cm3, 1 cm3, 2 cm3, 5 cm3 and 10 cm3 of the whole organ and wall of bladder and rectum were computed for all fractions. The impact of interstitial needles and OAR volume were explored.
30 25 20 15
Whole organ
10
Organ wall
5 0 0
0.5
1
Relave dose
Statistical analysis
(B)
The ratio of whole organ to wall dose and the absolute difference were determined for each dosimetric parameter. The ratios and absolute differences for those treated (a) with or without interstitial needles, and (b) with full vs. empty bladder were compared using the Wilcoxon rank sum test. The correlation between rectum or bladder volume with whole organ to wall dose ratios were evaluated by Spearman’s correlation coefficient. Since 10 parameters (ratios and absolute differences) were tested per organ, the a-level for rejecting the null hypothesis of no difference/correlation was set at 0.005 (Bonferroni’s correction). Results Of the 62 patients included in this study, 79% of patients had squamous cell carcinoma and 50% of patients had FIGO stage IIB–IIIB disease. The mean CTVHR was 31 ± 14 cm3 (SD); the combined EBRT and brachytherapy mean CTVHR D90% was 93 ± 4 Gy10. Rectum whole organ and wall volumes for fraction 1 were
Fig. 1. Example of a patient’s (A) dose–volume histograms for the bladder and rectum whole organ versus wall (where x-axis was normalized to the prescription dose of 7 Gy); and (B) corresponding dose distribution (red shaded contour = CTVHR; blue isodose line = 3.5 Gy, beige isodose line = 4.4 Gy, red isodose line = 7 Gy; and white isodose line = 14 Gy). The dose to 2 cm3 of the bladder and rectum whole organ contour is good estimate of dose to the respective wall. As the volume increases, the difference between the dose to the whole organ vs. wall increases, especially for reporting volumes > 10 cm3.
Please cite this article in press as: Gerber R et al. Comparison of dosimetric parameters derived from whole organ and wall contours for bladder and rectum in cervical cancer patients treated with intracavitary and interstitial brachytherapy. Radiother Oncol (2018), https://doi.org/10.1016/j.radonc.2018.01.015
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R. Gerber et al. / Radiotherapy and Oncology xxx (2018) xxx–xxx Table 1 Dosimetric parameters for fraction 1 for, intracavitary technique, intracavitary/interstitial technique, bladder full and bladder empty. Dosimetric parameter (mean ± SD)
Intracavitary (n = 30)
Intracavitary/interstitial (n = 32)
Bladder full (n = 12)
Bladder empty (n = 50)
Rectum Ratio of organ to wall dose (–) D0.1cm3 D1cm3 D2cm3 D5cm3 D10cm3
1.0 ± 0.004 1.0 ± 0.01 1.0 ± 0.03 1.1 ± 0.1 1.2 ± 0.1
1.0 ± 0.004 1.0 ± 0.03 1.0 ± 0.1 1.1 ± 0.1 1.2 ± 0.1
1.0 ± 0.002 1.0 ± 0.003 1.0 ± 0.01 1.1 ± 0.04 1.2 ± 0.1
1.0 ± 0.004 1.0 ± 0.02 1.0 ± 0.1 1.1 ± 0.1 1.2 ± 0.1
Absolute difference between organ and wall dose (Gy) 0.01 ± 0.02 D0.1cm3 D1cm3 0.02 ± 0.04 D2cm3 0.1 ± 0.1 0.2 ± 0.1 D5cm3 D10cm3 0.3 ± 0.2
0.01 ± 0.02 0.04 ± 0.1 0.1 ± 0.2 0.2 ± 0.2 0.3 ± 0.2
0.01 ± 0.01 0.01 ± 0.01 0.1 ± 0.1 0.2 ± 0.1 0.3 ± 0.1
0.01 ± 0.03 0.04 ± 0.1 0.1 ± 0.2 0.2 ± 0.2 0.4 ± 0.2
Bladder Ratio of organ to wall dose (–) D0.1cm3 D1cm3 D2cm3 D5cm3 D10cm3
1.0 ± 0.01 1.0 ± 0.03 1.1 ± 0.1 1.3 ± 0.3 1.7 ± 0.6
1.0 ± 0.01 1.0 ± 0.1 1.1 ± 0.1 1.5 ± 0.3* 2.3 ± 0.6*
1.0 ± 0.01 1.0 ± 0.03 1.0 ± 0.1 1.2 ± 0.2* 1.5 ± 0.4*
0.01 ± 0.1 0.1 ± 0.2 0.3 ± 0.4 0.8 ± 0.6 1.2 ± 0.6
0.01 ± 0.1 0.3 ± 0.3 0.6 ± 0.5 1.4 ± 0.6* 2.1 ± 0.4*
0.02 ± 0.1 0.1 ± 0.2 0.2 ± 0.3 0.6 ± 0.5* 0.9 ± 0.5*
1.0 ± 0.01 1.0 ± 0.04 1.1 ± 0.1 1.2 ± 0.2 1.6 ± 0.5
Absolute difference between organ and wall dose (Gy) D0.1cm3 0.01 ± 0.03 D1cm3 0.1 ± 0.3 D2cm3 0.3 ± 0.4 D5cm3 0.7 ± 0.6 D10cm3 1.1 ± 0.7
Abbreviations: D = minimum dose received by the specified volume of rectum or bladder. * p < 0.005 for bladder full vs. empty based on Wilcoxon’s test and Bonferroni’s correction.
Intracavitary compared to combined intracavitary and interstitial brachytherapy For the first application, 30 patients (48%) were treated with ring and tandem only and 32 patients (52%) were treated with ring, tandem, and interstitial needles. There were no significant differences in any of the bladder or rectum whole organ to wall dose ratios, nor absolute differences, between those treated with or without interstitial technique (Table 1). Subgroup analysis of 9 patients who had intracavitary brachytherapy for the first application but combined intracavitary/interstitial technique for the second application revealed similar ratios and absolute differences between two fractions (statistical testing not performed given the limited number of patients) (Table E2). Correlation with rectum or bladder whole organ volume Analysis of fraction 1 data for all 62 patients showed a weak positive correlation between the rectum whole organ volume and the ratio of whole organ to wall dose for D2cm3 and D10cm3 (r = 0.36, p = 0.004; and r = 0.38, p = 0.002, respectively). For bladder, analysis of fraction 1 data for all 62 patients showed a moderate positive correlation between whole organ volume and the ratios of whole organ to wall dose for D2cm3, D5cm3, and D10cm3 (r = 0.46, p = 0.002; r = 0.50, p < 0.001; and r = 0.65, p < 0.001, respectively). Bladder full compared to bladder empty The impact of a full bladder (12 patients) on the ratios and absolute differences was investigated. The ratios of whole organ to wall doses for bladder D5cm3 and D10cm3 were significantly higher for those treated with full than empty bladder (p < 0.005, Table 1). Similarly, the absolute differences between dose to whole organ and wall only for bladder D5cm3 and D10cm3 are also significantly higher for those treated with full bladder (mean D5cm3 absolute
difference 1.4 vs. 0.6 Gy, and D10cm3 2.1 vs. 0.9 Gy, respectively; p < 0.005, Table 1). The highest ratios and absolute differences (outliers) for D5cm3 and D10cm3 were observed in patients with bladder whole organ volume > 100 cm3. Discussion This study compared dosimetric parameters calculated from whole organ and wall contours for bladder and rectum in patients treated with ring and tandem with or without interstitial needles. There were no significant differences between those treated with or without interstitial needles. Our results for bladder and rectum D2cm3 are consistent with that from Wachter-Gerstner and Olszewska et al., who concluded that doses to the whole organ can be used instead of the wall for volumes < 5 cm3 in cervix patients treated with intracavitary brachytherapy [11,17]. However, our mean whole organ to wall dose ratios and standard deviations for the rectum appear lower than that in the Wachter-Gerstner study, where the mean D2cm3 ratio is 1.2 ± 0.1, D5cm3 1.6 ± 0.3, and D10cm3 2.1 ± 0.6 [11]. The larger volume of rectum in the Wachter-Gerstner study compared to ours (mean 58 ± 22 cm3 vs. 39 ± 13 cm3 for fraction 1, respectively) may explain the differences in the ratios between the studies, since we observe a weak positive correlation between the rectum volume and ratios. Given that the ratio of whole organ to wall dose for D5cm3 rectum (and some D10cm3 rectum) is 1.2 in our study (same as that for D2cm3 in the Wachter-Gerstner study), whole organ doses may potentially be good estimates of wall doses for up to 5 cm3 of the rectum if the rectum is not distended. This result may only apply to practices where only one HDR fraction is delivered per applicator insertion with bowel preparation before the procedure, and may not apply if the second HDR fraction is delivered the day after applicator insertion, with the patient immobilized and thereby higher likelihood of flatus and/or stool causing rectal distension. If our whole organ to wall dose ratio for D5cm3
Please cite this article in press as: Gerber R et al. Comparison of dosimetric parameters derived from whole organ and wall contours for bladder and rectum in cervical cancer patients treated with intracavitary and interstitial brachytherapy. Radiother Oncol (2018), https://doi.org/10.1016/j.radonc.2018.01.015
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OAR delineation in cervix brachytherapy
rectum (the most relevant parameter for predicting toxicity as per Kim et al. [14]) is validated by another study, D5cm3 can be more readily extracted from the whole organ contour and correlated with late toxicity. The uncertainties associated with whole organ versus organ wall contouring observed in our study are similar to that reported by Lang et al. when applying 2 HDR fractions for each applicator insertion compared to individual adaptive planning for each fraction [18], and smaller than that reported by Nesvacil et al. when analyzing inter-/intrafractional anatomical variations [19]. Since whole organ delineation is reliable and quicker than wall delineation, for practical reasons it is the recommended method by the GEC-ESTRO and ICRU89 for small volumes up to 2–3 cm3 [12,13]. We did not find significant differences in any of the bladder or rectum whole organ to wall dose ratios, nor absolute differences, between those treated with or without interstitial brachytherapy. This supports delineating the whole organ for cases treated with combined intracavitary/interstitial technique. As expected, the whole organ to wall dose ratios for bladder D5cm3 and D10cm3 are significantly higher for those treated with full bladder compared to empty bladder (p < 0.005). Bladder filling distends the bladder wall and increases the bladder volume, which results in the minimum dose of the wall for a large volume to be further away from the applicator/high-dose region and hence the larger whole organ to wall dose ratio. Therefore, wall contours should be used for planning, especially when the bladder is full. In conclusion, doses computed for whole organ from the external contour are good estimates of the doses in the wall for 2 cm3 of the bladder and rectum, and possibly for volumes up to 5 cm3 of the rectum if the rectum is not distended. There are no significant differences between those treated with or without interstitial needles in our study. This supports the practice of delineating the whole organ of rectum and bladder in patients treated with combined intracavitary/interstitial brachytherapy for D2cm3. Conflict of interest statement None. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.radonc.2018.01. 015. References [1] Han K, Milosevic M, Fyles A, Pintilie M, Viswanathan AN. Trends in the utilization of brachytherapy in cervical cancer in the United States. Int J Radiat Oncol Biol Phys 2013;87:111–9. [2] Lanciano RM, Martz K, Coia LR, Hanks GE. Tumor and treatment factors improving outcome in stage III-B cervix cancer. Int J Radiat Oncol Biol Phys 1991;20:95–100.
[3] Potter R, Georg P, Dimopoulos JC, et al. Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer. Radiother Oncol 2011;100:116–23. [4] Fokdal L, Sturdza A, Mazeron R, et al. Image guided adaptive brachytherapy with combined intracavitary and interstitial technique improves the therapeutic ratio in locally advanced cervical cancer: analysis from the retroEMBRACE study. Radiother Oncol 2016;120:434–40. [5] Mazeron R, Fokdal LU, Kirchheiner K, et al. Dose–volume effect relationships for late rectal morbidity in patients treated with chemoradiation and MRIguided adaptive brachytherapy for locally advanced cervical cancer: results from the prospective multicenter EMBRACE study. Radiother Oncol 2016;120:412–9. [6] Sturdza A, Potter R, Fokdal LU, et al. Image guided brachytherapy in locally advanced cervical cancer: improved pelvic control and survival in RetroEMBRACE, a multicenter cohort study. Radiother Oncol 2016;120:428–33. [7] Lindegaard JC, Fokdal LU, Nielsen SK, Juul-Christensen J, Tanderup K. MRIguided adaptive radiotherapy in locally advanced cervical cancer from a Nordic perspective. Acta Oncol 2013;52:1510–9. [8] Levitchi M, Charra-Brunaud C, Quetin P, et al. Impact of dosimetric and clinical parameters on clinical side effects in cervix cancer patients treated with 3D pulse-dose-rate intracavitary brachytherapy. Radiother Oncol 2012;103:314–21. [9] Mazeron R, Maroun P, Castelnau-Marchand P, et al. Pulsed-dose rate imageguided adaptive brachytherapy in cervical cancer: dose–volume effect relationships for the rectum and bladder. Radiother Oncol 2015;116:226–32. [10] Georg P, Potter R, Georg D, et al. Dose effect relationship for late side effects of the rectum and urinary bladder in magnetic resonance image-guided adaptive cervix cancer brachytherapy. Int J Radiat Oncol Biol Phys 2012;82:653–7. [11] Wachter-Gerstner N, Wachter S, Reinstadler E, et al. Bladder and rectum dose defined from MRI based treatment planning for cervix cancer brachytherapy: comparison of dose–volume histograms for organ contours and organ wall, comparison with ICRU rectum and bladder reference point. Radiother Oncol 2003;68:269–76. [12] Potter R, Haie-Meder C, Van Limbergen E, et al. Recommendations from gynaecological (GYN) GEC ESTRO working group (II): concepts and terms in 3D image-based treatment planning in cervix cancer brachytherapy-3D dose volume parameters and aspects of 3D image-based anatomy, radiation physics, radiobiology. Radiother Oncol 2006;78:67–77. [13] International Commission of Radiation Units and Measurements. ICRU report 89: prescribing, recording, and reporting brachytherapy for cancer of the cervix. J. ICRU 2013:13. [14] Kim TH, Kim JY, Sohn DK, et al. A prospective observational study with dose volume parameters predicting rectosigmoidoscopic findings and late rectosigmoid bleeding in patients with uterine cervical cancer treatment by definitive radiotherapy. Radiat Oncol 2013;8:28. [15] Ujaimi R, Milosevic M, Fyles A, et al. Intermediate dose–volume parameters and the development of late rectal toxicity after MRI-guided brachytherapy for locally advanced cervix cancer. Brachytherapy 2017. [16] Haie-Meder C, Potter R, Van Limbergen E, et al. Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group (I): concepts and terms in 3D image based 3D treatment planning in cervix cancer brachytherapy with emphasis on MRI assessment of GTV and CTV. Radiother Oncol 2005;74:235–45. [17] Olszewska AM, Saarnack AE, De Boer RW, Van Bunningen BNFM, Steggerda MJ. Comparison of dose–volume histograms and dose-wall histograms of the rectum of patients treated with intracavitary brachytherapy. Radiother Oncol 2001;61:83–5. [18] Lang S, Nesvacil N, Kirisits C, et al. Uncertainty analysis for 3D image-based cervix cancer brachytherapy by repetitive MR imaging: assessment of DVHvariations between two HDR fractions within one applicator insertion and their clinical relevance. Radiother Oncol 2013;107:26–31. [19] Nesvacil N, Tanderup K, Hellebust TP, et al. A multicentre comparison of the dosimetric impact of inter- and intra-fractional anatomical variations in fractionated cervix cancer brachytherapy. Radiother Oncol 2013;107:20–5.
Please cite this article in press as: Gerber R et al. Comparison of dosimetric parameters derived from whole organ and wall contours for bladder and rectum in cervical cancer patients treated with intracavitary and interstitial brachytherapy. Radiother Oncol (2018), https://doi.org/10.1016/j.radonc.2018.01.015