1. Introduction
Up to 50% of the high-risk prostate cancer patients treated with primary dose-escalated radiation therapy develop a biochemical recurrence within 10 years of treatment [
1- Heemsbergen W.D.
- Al-Mamgani A.
- Slot A.
- Dielwart M.F.H.
- Lebesque J.V.
Long-term results of the Dutch randomized prostate cancer trial: Impact of dose-escalation on local, biochemical, clinical failure, and survival.
,
2- Beckendorf V.
- Guerif S.
- Le Prisé E.
- Cosset J.M.
- Bougnoux A.
- Chauvet B.
- et al.
70 Gy versus 80 Gy in localized prostate cancer: 5-year results of GETUG 06 randomized trial.
]. In more than half of the patients with a recurrence detected on imaging, the recurrence is confined to the prostate and/or seminal vesicles [
[3]- Zumsteg Z.S.
- Spratt D.E.
- Romesser P.B.
- Pei X.
- Zhang Z.
- Kollmeier M.
- et al.
Anatomic Patterns of Recurrence Following Biochemical Relapse in the Dose-Escalation Era for Prostate Patients Undergoing External Beam Radiotherapy.
]. A treatment option for local radiorecurrent prostate cancer is magnetic resonance imaging (MRI)-guided focal salvage high-dose-rate brachytherapy (FS-HDR-BT) [
4- Maenhout M.
- Peters M.
- van Vulpen M.
- Moerland M.A.
- Meijer R.P.
- van den Bosch M.A.A.J.
- et al.
Focal MRI-Guided Salvage High-Dose-Rate Brachytherapy in Patients With Radiorecurrent Prostate Cancer.
,
5A review of salvage treatment options for disease progression after radiation therapy for localized prostate cancer.
]. With FS-HDR-BT, patients are treated in a single treatment session with a dose of 19 Gy to the clinical target volume (CTV). The radiation is delivered locally through catheters inserted via the perineum into the prostate using an Ir-192 source [
[4]- Maenhout M.
- Peters M.
- van Vulpen M.
- Moerland M.A.
- Meijer R.P.
- van den Bosch M.A.A.J.
- et al.
Focal MRI-Guided Salvage High-Dose-Rate Brachytherapy in Patients With Radiorecurrent Prostate Cancer.
]. However, due to the invasiveness of the treatment and the need for spinal anesthesia, not all patients are eligible. Furthermore, a non-invasive treatment option will increase patient comfort.
The recent clinical introduction of magnetic resonance linear accelerator (MR-Linac) systems opens up a non-invasive treatment possibility that uses stereotactic body radiotherapy (SBRT) [
[6]- Raaymakers B.W.
- Jurgenliemk-Schulz I.M.
- Bol G.H.
- Glitzner M.
- Kotte A.N.T.J.
- van Asselen B.
- et al.
First patients treated with a 1.5 T MRI-Linac: clinical proof of concept of a high-precision, high-field MRI guided radiotherapy treatment.
]. A MR-Linac integrates a MRI scanner with a linear accelerator [
[7]- Lagendijk J.J.W.
- Raaymakers B.W.
- van Vulpen M.
The Magnetic Resonance Imaging-Linac System.
]. This technology enables the visualization of the anatomy before and during treatment, allowing for daily adjustment of treatment plans [
8de Muinck Keizer DM, Pathmanathan AU, Andreychenko A, Kerkmeijer LGW, van der Voort van Zyp JRN, Tree AC, et al. Fiducial marker based intra-fraction motion assessment on cine-MR for MR-Linac treatment of prostate cancer. Phys Med Biol 2019;64:07NT02. https://doi.org/10.1088/1361-6560/ab09a6.
,
9- Kontaxis C.
- Bol G.H.
- Lagendijk J.J.W.
- Raaymakers B.W.
A new methodology for inter- and intrafraction plan adaptation for the MR-linac.
]. This leads to improved targeting compared to current conventional SBRT. Consequently, radiation-oncologists can reduce safety margins and deliver a higher dose per fraction. These aspects could make the MR-Linac a viable non-invasive alternative to FS-HDR-BT for treatment of radiorecurrent prostate cancer in a single fraction.
We conducted a planning study to evaluate the feasibility of delivering a single 19 Gy dose to a locally radiorecurrent prostate cancer lesion using a 1.5 Tesla MR-Linac system. The MR-Linac plans were compared to the clinically delivered FS-HDR-BT plans.
4. Discussion
We performed a comparative planning study to evaluate the feasibility of delivering a single 19 Gy dose to a local recurrent prostate cancer lesion using a 1.5 Tesla MR-Linac system. The simulated MR-Linac plans were compared to clinically delivered FS-HDR-BT plans. Both treatment planning techniques showed comparable target coverage (see
Table 2), though with both techniques the target dose of 19 Gy was not reached for some cases. The SBRT technique combined with the additional 1 mm PTV margin resulted in a higher median dose to both the urethra and rectum for the MR-Linac plans. However, no OAR constraints were violated. Delivering a single 19 Gy dose to a recurrent prostate cancer lesion with acceptable target dose coverage, while respecting OAR constraints, thus seems feasible on a MR-Linac.
To our knowledge, no studies have investigated the feasibility of focal salvage SBRT to deliver a single fraction 19 Gy dose to an intraprostatic lesion in the recurrent setting with corresponding OAR constraints. Henderson et al. reported a planning study on single session treatment using SBRT and a 3 mm PTV margin [
[16]- Henderson D.
- Tree A.
- van As N.
Single Fraction External Beam Radiotherapy for Localised Prostate Cancer: a Planning Study.
]. They prescribed 15 Gy and 19 Gy to ≥ 95% and 65–75% of the PTV, respectively, with a boost of 21 Gy to ≥ 95% of the MRI-visible intraprostatic lesion plus a 3 mm margin. The median rectal D2cm
3 was 14.4 Gy and median urethral V20.8 was 20.8%. However, the different treatment setting with different OAR constraints makes it hard to extrapolate these results to our study. Currently, Zilli et al. are investigating the delivery of a single 19 Gy dose to the whole prostate gland and two-thirds of the seminal vesicles with urethra sparing (down to 17 Gy) in a primary setting [
17- Zilli T.
- Koustouvelis N.
- Miralbell R.
- Scorsetti M.
- Franzese C.
- D’Agostino G.R.
- et al.
ONE SHOT - single shot radiotherapy for localized prostate cancer: Study protocol of a single arm, multicenter phase I/II trial.
,
18- Zilli T.
- Franzese C.
- Bottero M.
- Giaj-Levra N.
- Förster R.
- Zwahlen D.
- et al.
Single fraction urethra-sparing prostate cancer SBRT: Phase I results of the ONE SHOT trial.
]. For bladder and rectum constraints, they use V20Gy < 1 cm
3. Again, because of the different setting and constraints, the results of this study are not directly comparable to our results.
OAR constraints were met for all MR-Linac plans. We found a higher median urethral and rectal dose with the MR-Linac plans compared to FS-HDR-BT. This can be explained by the more gradual dose fall-off with SBRT and the larger PTV. Besides a higher rectum D1cm
3, the mean dose to the rectum is also likely to increase. However, limited data is available on toxicity in patients treated with focal salvage radiotherapy. In our FS-HDR-BT group, grade 2 and higher gastro-intestinal (GI) toxicity was extremely low, with no grade 3 GI toxicity so far and only 4% new-onset grade 2 GI toxicity, as reported by Van Son et al. [
[19]- van Son M.J.
- Peters M.
- Moerland M.A.
- Lagendijk J.J.W.
- Eppinga W.S.C.
- Shah T.T.
- et al.
MRI-Guided Ultrafocal Salvage High-Dose-Rate Brachytherapy for Localized Radiorecurrent Prostate Cancer: Updated Results of 50 Patients.
]. Although rectal dose is slightly higher with SBRT, it is still below the constraint and therefore low GI toxicity is expected. Bladder D1cm
3 and D2cm
3 were comparable for FS-HDR-BT and MR-Linac. This is probably caused by the more cranial position of the bladder with respect to the prostate and therefore this organ is easier to avoid with SBRT than the rectum. Again, the differences were quite small and probably clinically irrelevant. Nevertheless, prospective studies should assess this.
As expected, larger volumes receiving 150% or 200% of the prescribed dose were reached with FS-HDR-BT. A means to increase the volume receiving high dose levels using a MR-Linac might be to include an additional – higher – dose prescription to the GTV. A higher dose to the tumor potentially leads to longer biochemical progression-free survival (BPFS). However, the exact relationship between these high-dose volumes and BPFS in this patient group has to be established. Also, especially in this patient group with recurrent prostate cancer, radioresistance can play a role in oncologic outcomes of the treatment. Overall BPFS ranges between 47% and 54% at 5-year follow-up and a recent update by Van Son et al. showed that 73% of the intraprostatic recurrences after FS-HDR-BT occurred in-field [
19- van Son M.J.
- Peters M.
- Moerland M.A.
- Lagendijk J.J.W.
- Eppinga W.S.C.
- Shah T.T.
- et al.
MRI-Guided Ultrafocal Salvage High-Dose-Rate Brachytherapy for Localized Radiorecurrent Prostate Cancer: Updated Results of 50 Patients.
,
20Van Son M, Peters M, Moerland M, Kerkmeijer L, Lagendijk J, Van der Voort van Zyp J. Focal salvage treatment of radiorecurrent prostate cancer: A narrative review of current strategies and future perspectives. Cancers (Basel) 2018;10:480. https://doi.org/10.3390/cancers10120480.
]. Accordingly, this may imply that treatment of these tumors might benefit from an increased dose. Dose escalation and/or fractionation could improve oncologic outcomes, but may go hand-in-hand with increased acute toxicity as suggested by Murgic et al. [
[21]- Murgic J.
- Morton G.
- Loblaw A.
- D’Alimonte L.
- Ravi A.
- Wronski M.
- et al.
Focal Salvage High Dose-Rate Brachytherapy for Locally Recurrent Prostate Cancer After Primary Radiation Therapy Failure: Results From a Prospective Clinical Trial.
]. If future study results demonstrate improved oncologic outcomes by applying e.g. two or three fractions, the MR-Linac is a more attractive treatment modality due to both the non-invasiveness and easier logistics.
Stratifying the target dose by tumor location showed areas with higher and lower median D95%. However, the low numbers complicate drawing conclusions about these observations. Obviously, reaching target coverage strongly depends on the anatomy and therefore a decision should be made for each patient individually.
This study has several strengths. We included 30 patients with various tumor locations and sizes, thereby showing the feasibility in a non-selected patient group comparable to the target population. Secondly, from a FS-HDR-BT perspective, we used clinically delivered plans, which reflect the real capabilities of the FS-HDR-BT treatment modality.
Conversely, a limitation of this study is the fact that the MR-Linac plans are optimal plans based on several assumptions. Firstly, we have used a 1 mm PTV margin. As discussed in the materials and methods section, this 1 mm margin has to account for additional uncertainty due to intrafraction prostatic motion and geometrical (in)accuracy that are introduced with the use of a MR-Linac system compared to FS-HDR-BT. Based on the mentioned prostate tracking algorithm and adaptive treatment planning systems that have been developed at our department, this 1 mm margin seems to be achievable [
9- Kontaxis C.
- Bol G.H.
- Lagendijk J.J.W.
- Raaymakers B.W.
A new methodology for inter- and intrafraction plan adaptation for the MR-linac.
,
11de Muinck Keizer DM, Kerkmeijer LGW, Maspero M, Andreychenko A, van der Voort van Zyp JRN, van den Berg CAT, et al. Soft-tissue prostate intrafraction motion tracking in 3D cine-MR for MR-guided radiotherapy. Phys Med Biol 2019;64:235008. https://doi.org/10.1088/1361-6560/ab5539.
,
13- Kontaxis C.
- Bol G.H.
- Stemkens B.
- Glitzner M.
- Prins F.M.
- Kerkmeijer L.G.W.
- et al.
Towards fast online intrafraction replanning for free-breathing stereotactic body radiation therapy with the MR-linac.
,
14- Kontaxis C.
- Bol G.H.
- Lagendijk J.J.W.
- Raaymakers B.W.
DeepDose: towards a fast dose calculation engine for radiation therapy using deep learning.
]. Since interobserver contouring variability of the target is present in FS-HDR-BT as well, we do not expect this to lead to additional inaccuracy with MR-Linac treatments. Also, we believe that the full potential of MR-Linac systems lies in achieving these very small PTV margins that are not possible with conventional systems. Based on our prostate motion analyses, 3 to 4 mm margins are sufficient for current prostate cancer treatment without intra-fraction adaptation [
[12]- de Muinck Keizer D.M.
- Kerkmeijer L.G.W.
- Willigenburg T.
- van Lier A.L.H.M.W.
- den Hartogh M.D.
- van der Voort van Zyp J.R.N.
- et al.
Prostate intrafraction motion during the preparation and delivery of MR-guided radiotherapy sessions.
]. Enlarging the PTV margin in our study to i.e. 3 or 5 mm would thus not make full use of the MR-Linac system’s capabilities that distinguish it from conventional cone-beam CT linear accelerators. Still, this will remain hypothetical until it is technically possible to combine all the aforementioned developments into a clinically released system. Another limitation is the fact that we only had full field-of-view CT scans available for MR-Linac treatment planning. The registration between the intraoperative MRI and the CT scan and the contour propagation could lead to differences in the exact dose distributions. However, these potential differences were assumed to be minor and have no impact on the planning comparison study. Thirdly, we used FS-HDR-BT OAR constraints for our evaluation. We assessed the highest dose to small volumes (1 cm
3) for both the rectum and bladder. Contrary to FS-HDR-BT, mean dose to OAR is generally higher with external beam radiotherapy due to the more gradual dose fall-off. However, delivery of a single 19 Gy dose to a focal recurrent tumor using a volumetric modulated arch therapy (VMAT)-like technique resembles SBRT. Several studies on ultra-hypofractionated and single session radiotherapy for prostate cancer use only high-dose to low-volume constraints, thereby showing low toxicity rates [
18- Zilli T.
- Franzese C.
- Bottero M.
- Giaj-Levra N.
- Förster R.
- Zwahlen D.
- et al.
Single fraction urethra-sparing prostate cancer SBRT: Phase I results of the ONE SHOT trial.
,
22- Zilli T.
- Scorsetti M.
- Zwahlen D.
- Franzese C.
- Förster R.
- Giaj-Levra N.
- et al.
ONE SHOT - single shot radiotherapy for localized prostate cancer: Study protocol of a single arm, multicenter phase I/II trial.
,
23- Widmark A.
- Gunnlaugsson A.
- Beckman L.
- Thellenberg-Karlsson C.
- Hoyer M.
- Lagerlund M.
- et al.
Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer: 5-year outcomes of the HYPO-RT-PC randomised, non-inferiority, phase 3 trial.
,
24- Musunuru H.B.
- Quon H.
- Davidson M.
- Cheung P.
- Zhang L.
- D’Alimonte L.
- et al.
Dose-escalation of five-fraction SABR in prostate cancer: Toxicity comparison of two prospective trials.
]. Accordingly, we argue that D1cm
3 is a sensible and important parameter allowing for comparison between the two treatment modalities. Fourthly, due to the small stratified sample sizes, we were unable to draw any definitive conclusions from the dosimetric analysis per tumor location. Lastly, by using the intra-operative delineations from the FS-HDR-BT treatment, we took into account the effect of volume changes (edema) that might have occurred during brachytherapy due to the insertion of catheters. While no volume changes will occur with MR-Linac treatment, we used the same delineations for MR-Linac treatment planning. Therefore, the volumes might not be completely representative for MR-Linac treatment. However, for a fair comparison of the dose distributions, no adaptations were made to the delineations to include identical target volumes for both treatment plans.
In conclusion, we showed that for the majority of the patients treated with FS-HDR-BT, we could create an acceptable and comparable MR-Linac plan. This demonstrated the feasibility of SBRT treatment planning for radiorecurrent prostate cancer using a single 19 Gy dose on a 1.5 Tesla MR-Linac system, while respecting FS-HDR-BT OAR constraints. Hence, MR-Linac systems may provide a non-invasive alternative to FS-HDR-BT. Research should be conducted on the necessity of the larger high-dose volumes achieved in FS-HDR-BT, which may favor oncological outcomes in the long-term. Before clinical application of salvage MR-Linac treatment, real-time intra-fraction adaptation and dose calculation should be technically enabled, and clinical feasibility has to be tested in early phase clinical trials.
Article info
Publication history
Published online: August 07, 2020
Accepted:
July 23,
2020
Received in revised form:
June 9,
2020
Received:
April 16,
2020
Copyright
© 2020 The Authors. Published by Elsevier B.V. on behalf of European Society of Radiotherapy & Oncology.