Virtual modelling of novel applicator prototypes for cervical cancer brachytherapy

Brachytherapy (BT) is an essential component of treatment for locally advanced cervical cancer. Historically, X ray-based BT has been used, resulting in suboptimal disease control and toxicity rates, especially in advanced tumours.^1-5 Currently, image guided adaptive brachytherapy (IGABT) is being increasingly implemented worldwide. This modern technique is based on geometric individualization of the BT implant, sectional imaging, computerized treatment planning and remote afterloading technology.⁶ The concept of IGABT enables tight control over dose distribution in the tissues and personalized adaptation of treatment according to individual tumour size, topography and relation to the organs at risk (OAR). Consequently, dose escalation to the target volume is achieved, while respecting OAR dose constraints. Dosimetric advantages of IGABT over conventional 2D BT are well documented and are reflected in superior clinical outcomes.^7-16

Even with the most sophisticated treatment planning technology, optimal placement of source channels in the target volume remains a precondition for the success of BT. The ability to compensate for inadequacies of suboptimal insertion by optimization of source dwell-times and dwell-positions is limited. Standard intracavitary (IC) applicators for BT of cervical cancer do not always enable an acceptable balance between the coverage of the target volume and dose to the OAR.¹⁷ In patients with unfavourable tumour topography and/or gross residual disease extending beyond the reach of standard dose distribution, parts of the tumour cannot be covered with the prescribed dose without exceeding OAR tolerance. This leads to dosimetric cold spots in the tumour that predispose to treatment failure.^{18, 19} Recently developed intracavitary and interstitial (IC/IS) applicators for transvaginal placement of parallel parametrial needles allow for moderate lateral displacement of prescribed isodose.^20-23 While this leads to favourable therapeutic ratio in majority of cases, there is substantial proportion of challenging tumours which require alternative techniques for optimal outcome. Systematic assessment of dosimetric characteristics of currently available IC and IC/IS applicators or novel prototypes has not been performed so far. Theoretically, an ideal BT applicator would enable standardized and reproducible insertion of the IC and IS channels in optimal geometries, allowing for complete coverage of any tumour encountered in clinical practice. In this manuscript we present an innovative approach to evidence-based applicator development, using the method of Target-volume Density Mapping (TDM). TDM methodology was consequently applied in multi-institutional setting and promising preliminary outcome was presented.²⁴ Publication of the final results of this analysis is pending.

We conducted this study as a part of a wider applicator development project, performed by the international Gyn GEC ESTRO network. The work presented here is entirely technical, focusing merely on the software development and specification of related methodology. No patient information was used during this work. The developed methodology was consequently used in substudies on patients, included in the multi-institutional EMBRACE and retroEMBRACE protocols. These protocols were approved by the institutional re-view boards / ethical committees of participating centres. Promising preliminary results of this analysis were presented, while the publication of the final results is pending.²⁴ In the present manuscript, only the theoretical concept of software-based methodology for TDM generation is detailed.

Multidisciplinary task group from the Institute of Oncology Ljubljana and the University of Primorska, Faculty of Mathematics, was formed in 2009 to propose methodological framework for evidence based applicator modelling. The group consisted of an experienced radiation oncologist, a medical physicist and a computer scientist. The activities of the group were arbitrarily divided into (1) TDM software development and (2) Applicator modelling.

In our present project, we developed CAT 2 software for TDM generation and related post-processing methodology. Our method enables evidence-based modelling of novel IC/IS applicator prototypes and in-silico testing of existent devices. The proposed approach is based on analysis of pooled spatial information of target volumes from a representative sample of patients in the “applicator-eye view”.Lessons learned from historical evolution of applicators are essential for optimal utilization of modern development strategies, including our TDM method. Historical Paris and Stockholm techniques date back approximately 100 years.^26-28 The applicators consisted of a rubber tandem and a pair of colpostats (Paris technique) or flat vaginal box (Stockholm method), pre-loaded with ²²⁶Ra. In the 1930’s, the Manchester system was developed, introducing the point A and the applicator which was geometrically similar to its predecessors.²⁹ Nowadays, fixed geometry of uterine tandem and vaginal components (ovoids, cylinders or ring) enables reproducible insertion and reliable treatment using small sealed sources and afterloading technology. Standard loading patterns of modern applicators mimic the historical patterns based on milligram-hours of ²²⁶Ra tradition.³⁰ In topographically unfavourable tumours, optimization of loading can expand the prescribed dose for up to approximately 4 mm at the point A level.¹⁷ Target volumes that extend beyond this region and cases with unfavourable OAR topography pose a challenge to standard IC techniques. Applicators with static shielding in the ovoids were developed to improve the therapeutic ratio by reducing the irradiation of the OAR and their dosimetric impact was studied extensively.^31-34 Use of shielded devices outside the context of IGABT and model-based dose calculation algorithms may result in unintentional shielding of the target volume and uncertainties regarding the OAR doses.³² Emerging technologies, including static adjustable shielding and dynamic modulated BT with rotating paddle, can achieve highly conformal dose distributions in large targets of complex shapes.^35-37 However, when used in pure IC BT, directional modulation of intensity may lead to excessively high doses near the applicator along the emission window axis.³⁶ These techniques need to stand the test of further studies before their routine implementation. Dynamic shielding may play an important role in the future, especially if applied in combination with IC/IS insertion technique.³⁷ In summary, the exciting technological developments which we have witnessed over the past century failed to overcome the inherent physical limitations of IC BT.

Manufacturing of non-ferromagnetic applicators allowed for implementation of MRI based IGABT.^38-41 This can be regarded as the single most important advancement in the field of IC applicator development over last decades. IGABT offered an unprecedented opportunity to assess limitations of standard IC applicators and design improved IC/IS prototypes. TDM methodology described in this manuscript is based on estimation of the impact of individual applicator adjustments on a single “virtual patient”, containing pooled information from a sample of patients. In contrast, the traditional paradigm of empirical development is based on analysis of applicator limitations in individual cases, followed by iterative process of technical improvements. Using the traditional paradigm, novel IC/IS applicators were developed recently. Dimopoulos et al. introduced the Vienna tandem & ring applicator in which the ring serves as template for insertion of parallel needles into the parametria.²⁰ In their first report, 170 needles were inserted in 22 patients. The mean depth of insertion was only 37 +/-7 mm and the mean difference between planned and actual needle tip positions was sub-millimetric. Due to the use of blunt needles and short needle tracks, no organ perforations were identified and only 8.8% of the needles were outside the CTV_HR.²⁰ Tandem & ovoids applicator underwent similar evolution, resulting in the Utrecht applicator with comparable geometric, clinical and dosimetric characteristics.^{22, 23} IGABT with these application techniques enables moderate expansion and individual shaping of the isodose distribution, leading to improved dosimetric and clinical outcome.^{13, 14, 17, 22, 23} However, tumours with major extra-cervical infiltration at time of BT that extends beyond dosimetric reach of these applicators remain to pose a special challenge (i.e. infiltration of sacrouterine ligaments and distal parametria).

TDM-based methodology allows for objective quantification of IC and IC/IS applicator characteristics. By studying the impact of implant-geometry adjustments, prototypes of novel applicators that are theoretically capable of covering any target volume can be generated. Our method has been endorsed by the Gynaecological GEC ESTRO Network and preliminary results of its implementation in a multi-centre setting have been published in abstract form.²⁴ In this study, CTV_HR delineations from a representative sample of 264 patients were used to generate a TDM. Standard IC and Vienna IC/IS applicators achieved coverage of around 60% and 95% IDC, respectively. Prototypes, able of covering the remaining 5% of most challenging IDCs were proposed by adding virtual oblique needles to the Vienna applicator.²⁴ The impact of applicator geometries and dose optimization on RVR envelopes was not assessed in this preliminary report.

In the final analysis of this study, which is currently underway, two dose optimization models will be applied: standard and optimized. (1) In the standard model of dose planning, no RVRs will be assumed around the IDCs and no RVR-based optimization / reporting will be performed. This model therefore represents the most favourable theoretical scenario in terms of IDC dose-coverage. (2) In the optimized model, each IDC will be entirely surrounded by an RVR envelope and achieving the dose constraints for the RVR will be the absolute priority of dose optimization process. Optimized model is therefore the theoretical worst case scenario in terms of IDC coverage and it is practically never encountered in real clinical practice. In optimized model, the reported D2cc parameters for all the RVR envelopes will be the same, reflecting the RVR dose constraints. The utility of the proposed two-model approach is as follows: the two extreme planning approaches are the limiting scenarios, between which the actual clinical situations are expected. Consequently, the area between the two limiting IDC characteristic curves can be regarded as the “useful area” of a specific applicator. We believe that the development of new applicator prototypes, based on the TDM method will lead to further testing in clinical studies and finally commercial availability of safe, feasible and dosimetrically optimal devices, capable of covering the BT target volumes in any clinical situation. It can be expected that this will translate into further improved clinical outcomes of locally advanced cervical cancer management.

The emerging technology of personalized 3D printing of single-use IC/IS BT applicators is an exciting alternative to commercially available devices.⁴² Individual tailoring of the applicator size, shape and source channel geometry according to patient’s anatomy and tumour topography can be considered as the ultimate method to adaptive BT insertion. Advanced level of expertise, routine availability of pre-BT MRI, access to 3D printer and dedicated clinical time are required for implementation of 3D printing approach. Thus, standard IC/IS applicators remain to play an important role, especially in clinical settings with high incidence of cervical cancer and limited resources, making the TDM method presented here highly relevant.

In our method, the differences in tandem length and ring diameter are not taken into account during co-registration process, leading to a minimal overlap between the central parts of some target volumes with the reference applicator. Since central voxels are located in vicinity of the sources and high dose regions, this inconsistency bears minimal significance and is of limited interest for applicator development. The relevance of applicator development in the context of IGABT depends on accuracy of contouring of the target volume and organs at risk. There is a growing body of evidence that contouring uncertainties may be the weakest link in the process of IGABT.⁴³ Since our TDM methodology relies on import of individual target volume delineations, contouring uncertainties can undermine the validity of TDM-based applicator prototyping. Therefore, quality assurance of imported contours is essential for clinically relevant utilization of our method. There are three major aspects that need to be considered in this regard: (1) selection of target volume for TDM generation, (2) experience of radiation oncologists and (3) imaging modality for target volume delineation.

We developed methodology for applicator modelling based on pooled analysis of target volumes in reference applicator-eye-view. The system was validated using the phantom geometries. Recommendations to minimize uncertainties resulting from contouring variation were proposed. Using our method, virtual applicator prototypes capable of covering any target volume can be developed. Computer-based modelling represents the basic step in development of applicator prototypes which need to undergo further systematic assessment, including studies on clinical feasibility and safety. Our methodology was applied in multi-institutional setting and promising preliminary outcome published.²⁴ Final analysis of the data is currently underway.

The authors are grateful to Mr. Omar Hanuna, Institute of Oncology of Ljubljana for his valuable contribution to data collection, analysis and support during manuscript preparation. We are grateful to Prof. Peter Rogelj, PhD (University of Primorska, Faculty of Mathematics, Natural Sciences and Information Technologies, Koper, Slovenia) for the time and effort, invested in software development. We highly appreciate contributions of the Gyn GEC ESTRO Network, in particular the teams of Medical University of Vienna and Aarhus University Hospital, for their contribution to the presented work.