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Focal boost to residual gross tumor volume in brachytherapy for cervical cancer—A feasibility study
Brachytherapy
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(2017)
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Focal boost to residual gross tumor volume in brachytherapy for cervical cancerdA feasibility study Niluja Thiruthaneeswaran, Nicki Groom, Gerry Lowe, Linda Bryant, Peter J. Hoskin* Cancer Centre, Mount Vernon Hospital, Northwood, Middlesex, UK
ABSTRACT
PURPOSE: Image-guided plan optimization with MRI and CT for interstitial and intracavitary brachytherapy is an established technique in treating cervical cancer. The purpose of this study was to assess the feasibility of boosting the dose to the residual gross tumor volume (GTV-Tres) to 140% of the high-risk clinical target volume (HR-CTV) prescription. METHODS AND MATERIALS: Brachytherapy plans from 50 consecutive patients were analyzed in this study. All received external beam radiotherapy followed by brachytherapy (6 Gy 4 fraction or 7 Gy 4 fraction to HR-CTV). The original treatment plans were reoptimized escalating the GTV-Tres dose 140% of the original HR-CTV prescription dose to 8.4 Gy and 9.8 Gy/ per fraction, respectively, with the aim of achieving GTV-Tres V140 $ 90% and D98 $ 100 Gy. The HRCTV coverage and organ at risk (OAR) doseevolume histogram values were kept within the tolerance, which had been accepted for the original clinical plans. RESULTS: A total of 24 patients (48%) achieved the planning goal after reoptimization. There was no significant difference between the D2cc of the OARs of the clinical plan and the study boost plan. The factors having greatest impact on the delivered dose to the GTV-Tres are proximity of the OAR, intrauterine positioned outside the GTV-Tres, and suboptimal interstitial placement for boosting GTV-Tres. CONCLUSIONS: It is possible to boost the prescription dose to the GTV-Tres achieving 140% increase, which equates to an EQD2a/b510 O 100 Gy. Plans without both interstitial catheters and/or intrauterine within the GTV-Tres are most likely to be suboptimal. This planning study demonstrates that dose escalation to the GTV-Tres is feasible and further work into clinical application should be considered. Ó 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Cervical cancer; Dose escalation; Image-guided adaptive brachytherapy; Target volumes
Introduction The established standard of practice for locally advanced cervical cancer is definitive concurrent cisplatin-based chemoradiotherapy and brachytherapy (BT) (1, 2). BT is an integral component of the multimodality approach in managing cervical cancer with multiple published series demonstrating inferior local control and overall survival outcome when omitted (3, 4). In recent years, there has been significant improvement in imaging, which has seen
Received 7 March 2017; received in revised form 4 September 2017; accepted 18 September 2017. * Corresponding author. Cancer Centre, Mount Vernon Hospital, Rickmansworth Road, Northwood, Middlesex, HA6 2RN, UK. Tel.: þ442038262436. E-mail address: [email protected] (P.J. Hoskin).
the practice of BT planning move from 2D-based orthogonal images with dose prescribed to point A to highly conformal MRI volumeebased adaptive plans (5e7). The advantage of MRI-based planning is better differentiation of soft-tissue structures, enabling improved definition of target volume and organs at risk (OARs). In practice, often a fusion of CT and MRI imaging is used to aid applicator tracking. Image-guided adaptive brachytherapy not only has the advantage of tailored treatment but also recent publications demonstrate improved overall survival compared to historical controls (8). The use of interstitial (IS)-combined and intracavitary (IC)-combined insertions for plan optimization and improved doseevolume histogram (DVH) parameters have been reported (9). The greatest advantage of such a method is mainly seen with large residual disease after external beam radiation therapy (EBRT) where IC applicators alone
1538-4721/$ - see front matter Ó 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.brachy.2017.09.012
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are inadequate to achieve dose of $85 Gy EQD2Gy. IC-IS applicators also allow for greater flexibility in dose escalation of target volume and deescalation of surrounding organs ensuring OAR dose constraints are adhered to. Planning studies addressing feasibility of dose escalation to the HR-CTV are able to achieve an increase in dose by an average of one-third without the use of IS needles (10, 11). Analysis from retroEMBRACE reports a significant increase by an average 9 Gy to the HR-CTV D90 in their ICIS versus IC cohort (12). This is reflected in an improved local control rate increase of 5%. Contemporary data from the EMBRACE collaboration show the emerging importance of delivered dose to target volume with improved tumor control rates when the HRCTV D90 increases from 85 Gy to 90e95 Gy (13e15). This is reflected in single-institution series using a variety of different applicators and treatment with either high-doserate brachytherapy (HDR-BT) or pulsed dose rate brachytherapy (16e18). Further evidence for the role of dose escalation to the primary tumor comes from animal data demonstrating a clear tumor response when dose is increased to intratumoral hypoxic subvolumes. Thus, dose escalation to residual macroscopic tumor after external beam chemoradiation using MRI-guided focal brachytherapy boost may prove to be important in overcoming radiobiological resistance and achieving better local tumor control (19, 20). To date, there are limited published data in cervical cancer addressing the role of a focal boost to residual tumor at the time of BT. The purpose of this study was to assess the feasibility of a 40% dose escalation to the gross tumor volume at the time of BT (GTV-Tres) while maintaining current clinically acceptable dose to OARs. This dose escalation was chosen to achieve GTV-Tres D98 $ 100 Gy EQD2. Methods A retrospective cohort of 50 consecutive patients with histologically confirmed locally advanced cervical cancer (Federation Internationale de Gynecologie et d’Obstetrique 1B1eIVA) treated with definitive chemoradiation therapy followed by HDR-BT between July 2014 and December 2015 was included in this planning study. All patients were treated with EBRT to the pelvis to a dose of 45e50.2 Gy in 1.8e2 Gy fractions using megavoltage photons followed by HDR-BT (6 Gy 4 or 7 Gy 4). BT using either intrauterine tube and Vienna-style ring or Fletcher-style ovoid IC applicator with or without IS needles was performed under anesthetic using ultrasound guidance for implantation. Prior to insertion, an examination under anesthetic was conducted, and that along with the Week-5 T2-weighted MRI (Siemens Magnetom C! 0.35 T, Munich, Germany) was used to determine optimal IC/IC-IS configuration for HRCTV coverage. Patients without residual disease (i.e., complete response on Week-5 MRI) or where MRI at the time of BT was contraindicated were excluded from this planning study.
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BT planning After implantation of the IC applicators under general anesthetic, patients with just IC applicators underwent a planning MRI scan only. Patients implanted with IC and IS applicators had an MRI and CT scan (3-mm slice thickness with an additional reconstruction, from the same projection data, at 1-mm slice thickness). The addition of the CT scan in these cases allows for accurate tracking of the IS needles which are more difficult to visualize on MRI alone. The CT images were fused with the MRI for ease of OARs and disease contouring. Contouring of target volumes (HR-CTV, GTV-Tres) and OARs were done in accordance with The Groupe Europeen de CurietherapieEuropean Society for radiotherapy and oncology recommendations (Fig. 1) (21). The nonfocal boost HR-CTV region was defined as HR-CTV2 5 HR-CTV GTVTres. The dose was prescribed to the HR-CTV D90. For the purpose of this dosimetric study, the first-fraction planning images were used with the cumulative total dose extrapolated for fractions 2 e4 by simple multiplication assuming the same dosimetry for each fraction. The treatment plans were generated using Brachyvision (Version 11, Varian Medical Systems, Palo Alto, CA). The original HR-CTV planning aim of OAR constraints was to achieve an HR-CTV D90 $ 84 Gy, D2cc to bladder of 81.1 Gy, and 73.2 Gy for both rectum and sigmoid. Boost planning study For this boost planning study, the clinical plans that had been used to deliver treatment according to a dose prescribed to the HR-CTV were reoptimized to fit the criteria GTV-Tres V140 $ 90% and D98 $ 100 Gy. The planning goal for HR-CTV2 was V100 $ 90%. The dose prescribed to the GTV-Tres was 9.8 Gy for the 7 Gy per fraction plans and 8.4 Gy for the 6 Gy per fraction plans. This is a 40% increase of the current prescribed dose that equates to an increase of 60% in EQD2 of the BT component, giving a total EDQ2 including the external beam component of at least 100 Gy a/b10. The OAR parameters were kept to less than or equal to those that were accepted for the original clinical plans. The quality of the reoptimized plans was quantified using DVH parameters. Treatment plans were classed as either ‘‘pass’’ or ‘‘fail’’ based on the constraint objectives. All plans were reoptimized by a single experienced planner including predetermined factors affecting ‘‘pass’’ or ‘‘fail’’ rate. Results are presented using descriptive statistics with DVH parameters. Student’s two-tailed t test was performed using IBM SPSS v.24 (New York, NY) for OAR parameters and IC versus IC and IS with a significant p-value of !0.05. The linear quadratric model was used for radiobiological conversions with an a/b 5 10 Gy for tumor and 3.5 Gy (22, 23) for OARs using the formula EQD2Gy 5 DxGy [(x þ a/b)/(2 þ a/b)].
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Fig. 1. MRI and CT representative images of high-risk clinical target volume (HR-CTV), residual gross tumor volume (GTV-Tres), and the nonfocal boost region denoted as HR-CTV2.
Results A total of 50 consecutive patients were included in this study with a median age of 61.6 years (range 25e85.2). Most patients were Federation Internationale de Gynecologie et d’Obstetrique Stage 2B (62%) with squamous cell carcinoma (86%) being the predominate histology (Table 1). Thirty-five (70%) patients were implanted with IC-IS with the remainder being implanted with IC applicator alone. Target and critical structure volume parameters are outlined in Table 1. The mean, median, and range of the DVH parameters are shown in Table 2. Nineteen plans (38%) of the original plans achieved standard planning goals. In contrast for the boost plans, 24 plans (48%) met the preset planning goal criteria. On the original plans without the dedicated optimization, the V140 to the GTV-Tres, the volume on average was below the optimized plan with a median D98 GTV-Tres of 87.4% and 93.4%, respectively ( p 5 0.01). For the planning study, the HR-CTV2 V100 $ 90% was achieved in 35 patients
(70%). A total of 29 of 50 (58%) plans met the planning criteria for GTV-Tres D98 $ 100 Gy. There was no significant difference between the IC-IS and IC applicatorealone plans in achieving the planning goals (Table 2). The D2cc for OAR constraints achieved for the rectum, bladder, and sigmoid are shown in Table 3 without significant difference between the initial clinical plan and the focal boost plan. Factors affecting pass or fail rate of the failed plans were considered, including relative position of IC with respect to gross tumor volume (GTV), OAR limitation, GTV to HRCTV ratio, and IS catheter number and position of GTVTres (Fig. 2). All the plans that failed had more than one factor that was limiting dose escalation of GTV-Tres. OAR dose was the most commonly occurring limitation for not achieving the planning goals. Discussion There are limited published data on dose escalation to subvolumes within the HR-CTV representing residual
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Table 1 Baseline patient and treatment plan characteristics Patient characteristics
No. of patients (%)
(2017)
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Table 3 D2cc percentage constraints comparison for organs at risk of the original clinical and focal boost plans Percentage mean of D2cc constraint (SD)
Histology Squamous cell carcinoma Adenocarcinoma Adenosquamous FIGO stage 1b 2a 2b 3a 3b 4a 4b
43 (86) 6 (12) 1 (2) 3 3 31 3 5 2 3 Median
Age (years) Plan characteristics (cc) GTV-Tres HR-CTV2 HR-CTV1 OAR Rectum Bladder Sigmoid
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61.6
(6) (6) (62) (6) (10) (4) (6)
OAR
Clinical plan
Boost plan
p-value
Bladder Rectum Sigmoid
95.0 (25.5) 66.5 (23.2) 84.7 (23.1)
93.9 (21.4) 59.8 (23.0) 84.1 (24.0)
0.8 0.1 0.9
OAR 5 organ at risk.
Range 25e85.2
5.76 39.6 29.6
0.95e57 10.8e36.3 9.8e92.5
35.6 74.95 104.6
4.2e128.8 27.7e190.2 2.5e452.5
GTV-Tres 5 residual gross tumor volume; HR-CTV2 5 nonfocal boost high-risk clinical target volume; OAR 5 organ at risk; Federation Internationale de Gynecologie et d’Obstetrique.
disease after EBRT. To our knowledge, this is the first dosimetric article on the feasibility of increased prescription dose to the GTV-Tres as a focal boost. The EMBRACE collaborative group has reported on doseevolume response in their cohort of 488 patients. HR-CTV D90 of $85 Gy was associated with 94% and 86% local control for Stage II and Stage III disease, respectively. The GTV-Tres D100 of $85 Gy equated to local control rates of 94% (Stage II) and 79% (Stage III) (13). The greatest limitation to dose escalation of the target volume in image-guided adaptive brachytherapy is the proximity of the OARs. Only 48% of the GTV-Tres dose escalation plans ‘‘passed’’ the predetermined planning aims, and the use of IS needles did not facilitate the dose
escalation as expected. This could be partly attributed to the fact that the applicator positions were based on achieving optimal dose delivery to the original HR-CTV rather than any consideration of the position of a focal boost volume. The current EMBRACE II protocoleprescribed dose to the GTV-Tres is D98 O 90 Gy EQD2, a/ b 5 10 with a planning aim of 95 Gy (24). The clinical outcome of the EMBRACE II study will be valuable in informing current practice and the applicability of achieving dose escalation. A number of other key factors affecting pass rates of plans apart from OAR proximity were also identified. One was the position of the IC applicator relative to the GTV-Tres, where if the IC is abutting or lies within the GTV-Tres, it is easier to optimize the plan to meet the boost planning goals than in the cases where the IC position is offset from the GTV-Tres. If the IC is offset from the GTV-Tres and instead is positioned within the HR-CTV2, reasonably high dwell times are needed to cover GTV-Tres while maintaining adequate coverage of HR-CTV and OAR constraints. Another factor was !5-mm distance from GTV-Tres outline to the HR-CTV outline. In these cases, the dose gradient between the 140% isodose and the 100% isodose was too steep to cover the volumes differentially. To achieve a boost plan that fits the dose constraints, placement of applicators should take into account the position of the GTV-Tres, and where, for example, the cervical canal is not included in this volume, additional central catheters are required. This may be optimized using virtual preplanning (9, 25).
Table 2 Plan coverage with and without IS catheters for all plans and grouped into passed and failed plans based on the preset planning criteria Dose-volume parameters All plans HR-CTV2 V100 (%) GTV-Tres D98 (%) GTV-Tres V140 (%) Passed plans HR-CTV2 V100 (%) GTV-Tres D98 (%) GTV-Tres V140 (%) Failed plans HR-CTV2 V100 (%) GTV-Tres D98 (%) GTV-Tres V140 (%)
IC and IS Median (range)
IC Median (range)
p-value
94.2 (60e98.9) 133 (91.8e180.1) 94.7 (39.1e100)
94.7 (89.6e98.4) 128.7 (95.8e224.2) 92.6 (69.7e100)
0.01 0.11 0.24
95.6 (91.1e99.3) 140.2 (129.7e180.1) 98.15 (90.4e100)
95.3 (89.8e97.9) 149.2 (125.1e224.2) 99.7 (92.6e100)
0.64 0.101 0.578
87.1 (60e98.5) 110.5 (91.8e140.4) 80.7 (39.1e98)
94.7 (89.6e98.4) 116.9 (95.8e128.7) 88.1 (69.7e91.4)
0.068 0.589 0.269
IC 5 intracavitary; IS 5 interstitial; GTV-Tres 5 residual gross tumor volume; HR-CTV2 5 nonfocal boost high-risk clinical target volume.
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Number of plans
Factors affecng pass/fail rate of boost plans 20 18 16 14 12 10 8 6 4 2 0
Fail Pass
Fig. 2. Qualitative factors that influenced the pass rate of the plans. IU 5 intrauterine applicator; GTV 5 gross tumor volume (residual); CTV 5 clinical target volume (high risk); OAR 5 organ at risk.
There are several limitations to this study, one of which is volume of HR-CTV with a median ! 30 cm3. This is considered to be a smaller target size and may explain the nonsignificant result seen with IC/IS versus IC alone because the greatest benefit has been reported in larger target volumes (12e14). As expected, proximity of the OARs with adherence of the original clinical plan dose constraints was a considerable limitation to achieving the prescribed dose to the GTV-Tres. This study used the image sets from fraction 1 of the BT plans and as such did not take into consideration the interfraction variability or the geometric variations during treatment, which are encountered in clinical practice. Furthermore, vaginal dosimetry was not considered. The use of defined vaginal dose constraints in the future may further compound the ability to achieve adequate GTV dose escalation. It should be noted that we have used an a/b value of 3.5 for the OARs, whereas other literature including EMBRACE and ICRU 89 have advocated a value of 3. The absolute values for the OAR EQD2 doses cannot therefore be directly compared. MRI-guided treatment has now become the gold standard in BT for delineation of soft-tissue involvement and in particular defining parametrial extension as well as improved accuracy in defining OARs. Surgical series have demonstrated MRI to be more accurate than clinical examination on postoperative histopathology; however, evaluating tumor response after EBRT on MRI can be challenging (26e28). Functional imaging including fluorodeoxyglucose-positron emission tomography, diffusion-weighted MRI and dynamic contrast-enhanced MRI, and hypoxia imaging such as blood oxygen levele dependent MRI and 18F-AZA-PET may facilitate more accurate delineation of the residual tumor and relatively radioresistant regions (29e31).
Conclusion It is feasible to dose-escalate the GTV-Tres to 140% if IC and IS needles are optimally positioned. OAR position, size of margin between GTV-Tres and HR-CTV, and shape and position of GTV-Tres with respect to HR-CTV are also contributing factors. Focal boost to residual disease at the time of BT enables further dose escalation in an attempt to overcome poor prognostic factors in patients with locally advanced cervical cancer. References [1] Tanderup K, Eifel PJ, Yashar CM, et al. Curative radiation therapy for locally advanced cervical cancer: brachytherapy is not optional. Int J Radiat Oncol Biol Phys 2014;88:537e539. [2] Green J, Kirwan J, Tierney J, et al. Concomitant chemotherapy and radiation therapy for cancer of the uterine cervix. Cochrane Database Syst Rev 2005;CD002225. [3] Han K, Milosevic M, Fyles A, et al. Trends in the utilization of brachytherapy in cervical cancer in the United States. Int J Radiat Oncol Biol Phys 2013;87:111e119. [4] Logsdon MD, Eifel PJ. FIGO IIIB squamous cell carcinoma of the cervix: an analysis of prognostic factors emphasizing the balance between external beam and intracavitary radiation therapy. Int J Radiat Oncol Biol Phys 1999;43:763e775. [5] Tod M, Meredith W. A dosage system for use in the treatment of cancer of the uterine cervix. Br J Radiol 1938;11:809e824. [6] Tod M, Meredith WJ. Treatment of cancer of the cervix uteri, a revised Manchester method. Br J Radiol 1953;26:252e257. [7] Tanderup K, Viswanathan AN, Kirisits C, et al. Magnetic resonance image guided brachytherapy. Semin Radiat Oncol 2014;24:181e191. [8] 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: 116e123. [9] Fokdal L, Tanderup K, Hokland SB, et al. Clinical feasibility of combined intracavitary/interstitial brachytherapy in locally advanced
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N. Thiruthaneeswaran et al. / Brachytherapy cervical cancer employing MRI with a tandem/ring applicator in situ and virtual preplanning of the interstitial component. Radiother Oncol 2013;107:63e68. Menon G, Huang F, Sloboda R, et al. Practically achievable maximum high-risk clinical target volume doses in MRI-guided intracavitary brachytherapy for cervical cancer: a planning study. Brachytherapy 2014;13:572e578. Paton AM, Chalmers KE, Coomber H, et al. Dose escalation in brachytherapy for cervical cancer: impact on (or increased need for) MRI-guided plan optimisation. Br J Radiol 2012;85:e1249ee1255. 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; 120:434e440. Tanderup K, Fokdal LU, Sturdza A, et al. Effect of tumor dose, volume and overall treatment time on local control after radiochemotherapy including MRI guided brachytherapy of locally advanced cervical cancer. Radiother Oncol 2016;120:441e446. Jastaniyah N, Yoshida K, Tanderup K, et al. A volumetric analysis of GTVD and CTVHR as defined by the GEC ESTRO recommendations in FIGO stage IIB and IIIB cervical cancer patients treated with IGABT in a prospective multicentric trial (EMBRACE). Radiother Oncol 2016;120:404e411. Mazeron R, Castelnau-Marchand P, Escande A, et al. Tumor dosevolume response in image-guided adaptive brachytherapy for cervical cancer: A meta-regression analysis. Brachytherapy 2016;15:537e 542. Mazeron R, Castelnau-Marchand P, Dumas I, et al. Impact of treatment time and dose escalation on local control in locally advanced cervical cancer treated by chemoradiation and image-guided pulsed-dose rate adaptive brachytherapy. Radiother Oncol 2015; 114:257e263. Schmid MP, Kirisits C, Nesvacil N, et al. Local recurrences in cervical cancer patients in the setting of image-guided brachytherapy: A comparison of spatial dose distribution within a matched-pair analysis. Radiother Oncol 2011;100:468e472. Dimopoulos JC, Potter R, Lang S, et al. Dose-effect relationship for local control of cervical cancer by magnetic resonance image-guided brachytherapy. Radiother Oncol 2009;93:311e315. Hoskin PJ. Hypoxia dose painting in prostate and cervix cancer. Acta Oncol 2015;54:1259e1262.
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[20] Schutze C, Bergmann R, Bruchner K, et al. Effect of [(18)F]FMISO stratified dose-escalation on local control in FaDu hSCC in nude mice. Radiother Oncol 2014;111:81e87. [21] 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;74:235e245. [22] Tucker SL, Thames HD, Michalski JM, et al. Estimation of alpha/beta for late rectal toxicity based on RTOG 94-06. Int J Radiat Oncol Biol Phys 2011;81:600e605. [23] Skwarchuk MW, Jackson A, Zelefsky MJ, et al. Late rectal toxicity after conformal radiotherapy of prostate cancer (I): Multivariate analysis and dose-response. Int J Radiat Oncol Biol Phys 2000;47: 103e113. [24] Vienna DoRMUo. An international study on MRI-guided brachytherapy in locally advanced cervical cancer (EMBRACE II) 2017;. Available at: https://www.embracestudy.dk/. Accessed July 2017. [25] Petric P, Hudej R, Hanuna O, et al. MRI-assisted cervix cancer brachytherapy pre-planning, based on application in paracervical anaesthesia: Final report. Radiol Oncol 2014;48:293e300. [26] Jung DC, Ju W, Choi HJ, et al. The validity of tumour diameter assessed by magnetic resonance imaging and gross specimen with regard to tumour volume in cervical cancer patients. Eur J Cancer 2008;44:1524e1528. [27] Ozsarlak O, Tjalma W, Schepens E, et al. The correlation of preoperative CT, MR imaging, and clinical staging (FIGO) with histopathology findings in primary cervical carcinoma. Eur Radiol 2003; 13:2338e2345. [28] Mongula J, Slangen B, Lambregts D, et al. Predictive criteria for MRI-based evaluation of response both during and after radiotherapy for cervical cancer. J Contemp Brachytherapy 2016;8:181e188. [29] Mahajan A, Engineer R, Chopra S, et al. Role of 3T multiparametricMRI with BOLD hypoxia imaging for diagnosis and post therapy response evaluation of postoperative recurrent cervical cancers. Eur J Radiol Open 2016;3:22e30. [30] Fleming IN, Manavaki R, Blower PJ, et al. Imaging tumour hypoxia with positron emission tomography. Br J Cancer 2015;112:238e250. [31] Schmid MP, Mansmann B, Federico M, et al. Residual tumour volumes and grey zones after external beam radiotherapy (with or without chemotherapy) in cervical cancer patients. A low-field MRI study. Strahlenther Onkol 2013;189:238e244.
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Focal boost to residual gross tumor volume in brachytherapy for cervical cancerdA feasibility study Niluja Thiruthaneeswaran, Nicki Groom, Gerry Lowe, Linda Bryant, Peter J. Hoskin* Cancer Centre, Mount Vernon Hospital, Northwood, Middlesex, UK
ABSTRACT
PURPOSE: Image-guided plan optimization with MRI and CT for interstitial and intracavitary brachytherapy is an established technique in treating cervical cancer. The purpose of this study was to assess the feasibility of boosting the dose to the residual gross tumor volume (GTV-Tres) to 140% of the high-risk clinical target volume (HR-CTV) prescription. METHODS AND MATERIALS: Brachytherapy plans from 50 consecutive patients were analyzed in this study. All received external beam radiotherapy followed by brachytherapy (6 Gy 4 fraction or 7 Gy 4 fraction to HR-CTV). The original treatment plans were reoptimized escalating the GTV-Tres dose 140% of the original HR-CTV prescription dose to 8.4 Gy and 9.8 Gy/ per fraction, respectively, with the aim of achieving GTV-Tres V140 $ 90% and D98 $ 100 Gy. The HRCTV coverage and organ at risk (OAR) doseevolume histogram values were kept within the tolerance, which had been accepted for the original clinical plans. RESULTS: A total of 24 patients (48%) achieved the planning goal after reoptimization. There was no significant difference between the D2cc of the OARs of the clinical plan and the study boost plan. The factors having greatest impact on the delivered dose to the GTV-Tres are proximity of the OAR, intrauterine positioned outside the GTV-Tres, and suboptimal interstitial placement for boosting GTV-Tres. CONCLUSIONS: It is possible to boost the prescription dose to the GTV-Tres achieving 140% increase, which equates to an EQD2a/b510 O 100 Gy. Plans without both interstitial catheters and/or intrauterine within the GTV-Tres are most likely to be suboptimal. This planning study demonstrates that dose escalation to the GTV-Tres is feasible and further work into clinical application should be considered. Ó 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Cervical cancer; Dose escalation; Image-guided adaptive brachytherapy; Target volumes
Introduction The established standard of practice for locally advanced cervical cancer is definitive concurrent cisplatin-based chemoradiotherapy and brachytherapy (BT) (1, 2). BT is an integral component of the multimodality approach in managing cervical cancer with multiple published series demonstrating inferior local control and overall survival outcome when omitted (3, 4). In recent years, there has been significant improvement in imaging, which has seen
Received 7 March 2017; received in revised form 4 September 2017; accepted 18 September 2017. * Corresponding author. Cancer Centre, Mount Vernon Hospital, Rickmansworth Road, Northwood, Middlesex, HA6 2RN, UK. Tel.: þ442038262436. E-mail address: [email protected] (P.J. Hoskin).
the practice of BT planning move from 2D-based orthogonal images with dose prescribed to point A to highly conformal MRI volumeebased adaptive plans (5e7). The advantage of MRI-based planning is better differentiation of soft-tissue structures, enabling improved definition of target volume and organs at risk (OARs). In practice, often a fusion of CT and MRI imaging is used to aid applicator tracking. Image-guided adaptive brachytherapy not only has the advantage of tailored treatment but also recent publications demonstrate improved overall survival compared to historical controls (8). The use of interstitial (IS)-combined and intracavitary (IC)-combined insertions for plan optimization and improved doseevolume histogram (DVH) parameters have been reported (9). The greatest advantage of such a method is mainly seen with large residual disease after external beam radiation therapy (EBRT) where IC applicators alone
1538-4721/$ - see front matter Ó 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.brachy.2017.09.012
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are inadequate to achieve dose of $85 Gy EQD2Gy. IC-IS applicators also allow for greater flexibility in dose escalation of target volume and deescalation of surrounding organs ensuring OAR dose constraints are adhered to. Planning studies addressing feasibility of dose escalation to the HR-CTV are able to achieve an increase in dose by an average of one-third without the use of IS needles (10, 11). Analysis from retroEMBRACE reports a significant increase by an average 9 Gy to the HR-CTV D90 in their ICIS versus IC cohort (12). This is reflected in an improved local control rate increase of 5%. Contemporary data from the EMBRACE collaboration show the emerging importance of delivered dose to target volume with improved tumor control rates when the HRCTV D90 increases from 85 Gy to 90e95 Gy (13e15). This is reflected in single-institution series using a variety of different applicators and treatment with either high-doserate brachytherapy (HDR-BT) or pulsed dose rate brachytherapy (16e18). Further evidence for the role of dose escalation to the primary tumor comes from animal data demonstrating a clear tumor response when dose is increased to intratumoral hypoxic subvolumes. Thus, dose escalation to residual macroscopic tumor after external beam chemoradiation using MRI-guided focal brachytherapy boost may prove to be important in overcoming radiobiological resistance and achieving better local tumor control (19, 20). To date, there are limited published data in cervical cancer addressing the role of a focal boost to residual tumor at the time of BT. The purpose of this study was to assess the feasibility of a 40% dose escalation to the gross tumor volume at the time of BT (GTV-Tres) while maintaining current clinically acceptable dose to OARs. This dose escalation was chosen to achieve GTV-Tres D98 $ 100 Gy EQD2. Methods A retrospective cohort of 50 consecutive patients with histologically confirmed locally advanced cervical cancer (Federation Internationale de Gynecologie et d’Obstetrique 1B1eIVA) treated with definitive chemoradiation therapy followed by HDR-BT between July 2014 and December 2015 was included in this planning study. All patients were treated with EBRT to the pelvis to a dose of 45e50.2 Gy in 1.8e2 Gy fractions using megavoltage photons followed by HDR-BT (6 Gy 4 or 7 Gy 4). BT using either intrauterine tube and Vienna-style ring or Fletcher-style ovoid IC applicator with or without IS needles was performed under anesthetic using ultrasound guidance for implantation. Prior to insertion, an examination under anesthetic was conducted, and that along with the Week-5 T2-weighted MRI (Siemens Magnetom C! 0.35 T, Munich, Germany) was used to determine optimal IC/IC-IS configuration for HRCTV coverage. Patients without residual disease (i.e., complete response on Week-5 MRI) or where MRI at the time of BT was contraindicated were excluded from this planning study.
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BT planning After implantation of the IC applicators under general anesthetic, patients with just IC applicators underwent a planning MRI scan only. Patients implanted with IC and IS applicators had an MRI and CT scan (3-mm slice thickness with an additional reconstruction, from the same projection data, at 1-mm slice thickness). The addition of the CT scan in these cases allows for accurate tracking of the IS needles which are more difficult to visualize on MRI alone. The CT images were fused with the MRI for ease of OARs and disease contouring. Contouring of target volumes (HR-CTV, GTV-Tres) and OARs were done in accordance with The Groupe Europeen de CurietherapieEuropean Society for radiotherapy and oncology recommendations (Fig. 1) (21). The nonfocal boost HR-CTV region was defined as HR-CTV2 5 HR-CTV GTVTres. The dose was prescribed to the HR-CTV D90. For the purpose of this dosimetric study, the first-fraction planning images were used with the cumulative total dose extrapolated for fractions 2 e4 by simple multiplication assuming the same dosimetry for each fraction. The treatment plans were generated using Brachyvision (Version 11, Varian Medical Systems, Palo Alto, CA). The original HR-CTV planning aim of OAR constraints was to achieve an HR-CTV D90 $ 84 Gy, D2cc to bladder of 81.1 Gy, and 73.2 Gy for both rectum and sigmoid. Boost planning study For this boost planning study, the clinical plans that had been used to deliver treatment according to a dose prescribed to the HR-CTV were reoptimized to fit the criteria GTV-Tres V140 $ 90% and D98 $ 100 Gy. The planning goal for HR-CTV2 was V100 $ 90%. The dose prescribed to the GTV-Tres was 9.8 Gy for the 7 Gy per fraction plans and 8.4 Gy for the 6 Gy per fraction plans. This is a 40% increase of the current prescribed dose that equates to an increase of 60% in EQD2 of the BT component, giving a total EDQ2 including the external beam component of at least 100 Gy a/b10. The OAR parameters were kept to less than or equal to those that were accepted for the original clinical plans. The quality of the reoptimized plans was quantified using DVH parameters. Treatment plans were classed as either ‘‘pass’’ or ‘‘fail’’ based on the constraint objectives. All plans were reoptimized by a single experienced planner including predetermined factors affecting ‘‘pass’’ or ‘‘fail’’ rate. Results are presented using descriptive statistics with DVH parameters. Student’s two-tailed t test was performed using IBM SPSS v.24 (New York, NY) for OAR parameters and IC versus IC and IS with a significant p-value of !0.05. The linear quadratric model was used for radiobiological conversions with an a/b 5 10 Gy for tumor and 3.5 Gy (22, 23) for OARs using the formula EQD2Gy 5 DxGy [(x þ a/b)/(2 þ a/b)].
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Fig. 1. MRI and CT representative images of high-risk clinical target volume (HR-CTV), residual gross tumor volume (GTV-Tres), and the nonfocal boost region denoted as HR-CTV2.
Results A total of 50 consecutive patients were included in this study with a median age of 61.6 years (range 25e85.2). Most patients were Federation Internationale de Gynecologie et d’Obstetrique Stage 2B (62%) with squamous cell carcinoma (86%) being the predominate histology (Table 1). Thirty-five (70%) patients were implanted with IC-IS with the remainder being implanted with IC applicator alone. Target and critical structure volume parameters are outlined in Table 1. The mean, median, and range of the DVH parameters are shown in Table 2. Nineteen plans (38%) of the original plans achieved standard planning goals. In contrast for the boost plans, 24 plans (48%) met the preset planning goal criteria. On the original plans without the dedicated optimization, the V140 to the GTV-Tres, the volume on average was below the optimized plan with a median D98 GTV-Tres of 87.4% and 93.4%, respectively ( p 5 0.01). For the planning study, the HR-CTV2 V100 $ 90% was achieved in 35 patients
(70%). A total of 29 of 50 (58%) plans met the planning criteria for GTV-Tres D98 $ 100 Gy. There was no significant difference between the IC-IS and IC applicatorealone plans in achieving the planning goals (Table 2). The D2cc for OAR constraints achieved for the rectum, bladder, and sigmoid are shown in Table 3 without significant difference between the initial clinical plan and the focal boost plan. Factors affecting pass or fail rate of the failed plans were considered, including relative position of IC with respect to gross tumor volume (GTV), OAR limitation, GTV to HRCTV ratio, and IS catheter number and position of GTVTres (Fig. 2). All the plans that failed had more than one factor that was limiting dose escalation of GTV-Tres. OAR dose was the most commonly occurring limitation for not achieving the planning goals. Discussion There are limited published data on dose escalation to subvolumes within the HR-CTV representing residual
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Table 1 Baseline patient and treatment plan characteristics Patient characteristics
No. of patients (%)
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Table 3 D2cc percentage constraints comparison for organs at risk of the original clinical and focal boost plans Percentage mean of D2cc constraint (SD)
Histology Squamous cell carcinoma Adenocarcinoma Adenosquamous FIGO stage 1b 2a 2b 3a 3b 4a 4b
43 (86) 6 (12) 1 (2) 3 3 31 3 5 2 3 Median
Age (years) Plan characteristics (cc) GTV-Tres HR-CTV2 HR-CTV1 OAR Rectum Bladder Sigmoid
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61.6
(6) (6) (62) (6) (10) (4) (6)
OAR
Clinical plan
Boost plan
p-value
Bladder Rectum Sigmoid
95.0 (25.5) 66.5 (23.2) 84.7 (23.1)
93.9 (21.4) 59.8 (23.0) 84.1 (24.0)
0.8 0.1 0.9
OAR 5 organ at risk.
Range 25e85.2
5.76 39.6 29.6
0.95e57 10.8e36.3 9.8e92.5
35.6 74.95 104.6
4.2e128.8 27.7e190.2 2.5e452.5
GTV-Tres 5 residual gross tumor volume; HR-CTV2 5 nonfocal boost high-risk clinical target volume; OAR 5 organ at risk; Federation Internationale de Gynecologie et d’Obstetrique.
disease after EBRT. To our knowledge, this is the first dosimetric article on the feasibility of increased prescription dose to the GTV-Tres as a focal boost. The EMBRACE collaborative group has reported on doseevolume response in their cohort of 488 patients. HR-CTV D90 of $85 Gy was associated with 94% and 86% local control for Stage II and Stage III disease, respectively. The GTV-Tres D100 of $85 Gy equated to local control rates of 94% (Stage II) and 79% (Stage III) (13). The greatest limitation to dose escalation of the target volume in image-guided adaptive brachytherapy is the proximity of the OARs. Only 48% of the GTV-Tres dose escalation plans ‘‘passed’’ the predetermined planning aims, and the use of IS needles did not facilitate the dose
escalation as expected. This could be partly attributed to the fact that the applicator positions were based on achieving optimal dose delivery to the original HR-CTV rather than any consideration of the position of a focal boost volume. The current EMBRACE II protocoleprescribed dose to the GTV-Tres is D98 O 90 Gy EQD2, a/ b 5 10 with a planning aim of 95 Gy (24). The clinical outcome of the EMBRACE II study will be valuable in informing current practice and the applicability of achieving dose escalation. A number of other key factors affecting pass rates of plans apart from OAR proximity were also identified. One was the position of the IC applicator relative to the GTV-Tres, where if the IC is abutting or lies within the GTV-Tres, it is easier to optimize the plan to meet the boost planning goals than in the cases where the IC position is offset from the GTV-Tres. If the IC is offset from the GTV-Tres and instead is positioned within the HR-CTV2, reasonably high dwell times are needed to cover GTV-Tres while maintaining adequate coverage of HR-CTV and OAR constraints. Another factor was !5-mm distance from GTV-Tres outline to the HR-CTV outline. In these cases, the dose gradient between the 140% isodose and the 100% isodose was too steep to cover the volumes differentially. To achieve a boost plan that fits the dose constraints, placement of applicators should take into account the position of the GTV-Tres, and where, for example, the cervical canal is not included in this volume, additional central catheters are required. This may be optimized using virtual preplanning (9, 25).
Table 2 Plan coverage with and without IS catheters for all plans and grouped into passed and failed plans based on the preset planning criteria Dose-volume parameters All plans HR-CTV2 V100 (%) GTV-Tres D98 (%) GTV-Tres V140 (%) Passed plans HR-CTV2 V100 (%) GTV-Tres D98 (%) GTV-Tres V140 (%) Failed plans HR-CTV2 V100 (%) GTV-Tres D98 (%) GTV-Tres V140 (%)
IC and IS Median (range)
IC Median (range)
p-value
94.2 (60e98.9) 133 (91.8e180.1) 94.7 (39.1e100)
94.7 (89.6e98.4) 128.7 (95.8e224.2) 92.6 (69.7e100)
0.01 0.11 0.24
95.6 (91.1e99.3) 140.2 (129.7e180.1) 98.15 (90.4e100)
95.3 (89.8e97.9) 149.2 (125.1e224.2) 99.7 (92.6e100)
0.64 0.101 0.578
87.1 (60e98.5) 110.5 (91.8e140.4) 80.7 (39.1e98)
94.7 (89.6e98.4) 116.9 (95.8e128.7) 88.1 (69.7e91.4)
0.068 0.589 0.269
IC 5 intracavitary; IS 5 interstitial; GTV-Tres 5 residual gross tumor volume; HR-CTV2 5 nonfocal boost high-risk clinical target volume.
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Number of plans
Factors affecng pass/fail rate of boost plans 20 18 16 14 12 10 8 6 4 2 0
Fail Pass
Fig. 2. Qualitative factors that influenced the pass rate of the plans. IU 5 intrauterine applicator; GTV 5 gross tumor volume (residual); CTV 5 clinical target volume (high risk); OAR 5 organ at risk.
There are several limitations to this study, one of which is volume of HR-CTV with a median ! 30 cm3. This is considered to be a smaller target size and may explain the nonsignificant result seen with IC/IS versus IC alone because the greatest benefit has been reported in larger target volumes (12e14). As expected, proximity of the OARs with adherence of the original clinical plan dose constraints was a considerable limitation to achieving the prescribed dose to the GTV-Tres. This study used the image sets from fraction 1 of the BT plans and as such did not take into consideration the interfraction variability or the geometric variations during treatment, which are encountered in clinical practice. Furthermore, vaginal dosimetry was not considered. The use of defined vaginal dose constraints in the future may further compound the ability to achieve adequate GTV dose escalation. It should be noted that we have used an a/b value of 3.5 for the OARs, whereas other literature including EMBRACE and ICRU 89 have advocated a value of 3. The absolute values for the OAR EQD2 doses cannot therefore be directly compared. MRI-guided treatment has now become the gold standard in BT for delineation of soft-tissue involvement and in particular defining parametrial extension as well as improved accuracy in defining OARs. Surgical series have demonstrated MRI to be more accurate than clinical examination on postoperative histopathology; however, evaluating tumor response after EBRT on MRI can be challenging (26e28). Functional imaging including fluorodeoxyglucose-positron emission tomography, diffusion-weighted MRI and dynamic contrast-enhanced MRI, and hypoxia imaging such as blood oxygen levele dependent MRI and 18F-AZA-PET may facilitate more accurate delineation of the residual tumor and relatively radioresistant regions (29e31).
Conclusion It is feasible to dose-escalate the GTV-Tres to 140% if IC and IS needles are optimally positioned. OAR position, size of margin between GTV-Tres and HR-CTV, and shape and position of GTV-Tres with respect to HR-CTV are also contributing factors. Focal boost to residual disease at the time of BT enables further dose escalation in an attempt to overcome poor prognostic factors in patients with locally advanced cervical cancer. References [1] Tanderup K, Eifel PJ, Yashar CM, et al. Curative radiation therapy for locally advanced cervical cancer: brachytherapy is not optional. Int J Radiat Oncol Biol Phys 2014;88:537e539. [2] Green J, Kirwan J, Tierney J, et al. Concomitant chemotherapy and radiation therapy for cancer of the uterine cervix. Cochrane Database Syst Rev 2005;CD002225. [3] Han K, Milosevic M, Fyles A, et al. Trends in the utilization of brachytherapy in cervical cancer in the United States. Int J Radiat Oncol Biol Phys 2013;87:111e119. [4] Logsdon MD, Eifel PJ. FIGO IIIB squamous cell carcinoma of the cervix: an analysis of prognostic factors emphasizing the balance between external beam and intracavitary radiation therapy. Int J Radiat Oncol Biol Phys 1999;43:763e775. [5] Tod M, Meredith W. A dosage system for use in the treatment of cancer of the uterine cervix. Br J Radiol 1938;11:809e824. [6] Tod M, Meredith WJ. Treatment of cancer of the cervix uteri, a revised Manchester method. Br J Radiol 1953;26:252e257. [7] Tanderup K, Viswanathan AN, Kirisits C, et al. Magnetic resonance image guided brachytherapy. Semin Radiat Oncol 2014;24:181e191. [8] 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: 116e123. [9] Fokdal L, Tanderup K, Hokland SB, et al. Clinical feasibility of combined intracavitary/interstitial brachytherapy in locally advanced
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[20] Schutze C, Bergmann R, Bruchner K, et al. Effect of [(18)F]FMISO stratified dose-escalation on local control in FaDu hSCC in nude mice. Radiother Oncol 2014;111:81e87. [21] 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;74:235e245. [22] Tucker SL, Thames HD, Michalski JM, et al. Estimation of alpha/beta for late rectal toxicity based on RTOG 94-06. Int J Radiat Oncol Biol Phys 2011;81:600e605. [23] Skwarchuk MW, Jackson A, Zelefsky MJ, et al. Late rectal toxicity after conformal radiotherapy of prostate cancer (I): Multivariate analysis and dose-response. Int J Radiat Oncol Biol Phys 2000;47: 103e113. [24] Vienna DoRMUo. An international study on MRI-guided brachytherapy in locally advanced cervical cancer (EMBRACE II) 2017;. Available at: https://www.embracestudy.dk/. Accessed July 2017. [25] Petric P, Hudej R, Hanuna O, et al. MRI-assisted cervix cancer brachytherapy pre-planning, based on application in paracervical anaesthesia: Final report. Radiol Oncol 2014;48:293e300. [26] Jung DC, Ju W, Choi HJ, et al. The validity of tumour diameter assessed by magnetic resonance imaging and gross specimen with regard to tumour volume in cervical cancer patients. Eur J Cancer 2008;44:1524e1528. [27] Ozsarlak O, Tjalma W, Schepens E, et al. The correlation of preoperative CT, MR imaging, and clinical staging (FIGO) with histopathology findings in primary cervical carcinoma. Eur Radiol 2003; 13:2338e2345. [28] Mongula J, Slangen B, Lambregts D, et al. Predictive criteria for MRI-based evaluation of response both during and after radiotherapy for cervical cancer. J Contemp Brachytherapy 2016;8:181e188. [29] Mahajan A, Engineer R, Chopra S, et al. Role of 3T multiparametricMRI with BOLD hypoxia imaging for diagnosis and post therapy response evaluation of postoperative recurrent cervical cancers. Eur J Radiol Open 2016;3:22e30. [30] Fleming IN, Manavaki R, Blower PJ, et al. Imaging tumour hypoxia with positron emission tomography. Br J Cancer 2015;112:238e250. [31] Schmid MP, Mansmann B, Federico M, et al. Residual tumour volumes and grey zones after external beam radiotherapy (with or without chemotherapy) in cervical cancer patients. A low-field MRI study. Strahlenther Onkol 2013;189:238e244.