Dosimetric Impact of Interfraction Prostate and Seminal Vesicle Volume Changes and Rotation: A Post-Hoc Analysis of a Phase III Randomized Trial of MRI-Guided Versus CT-Guided Stereotactic Body Radiotherapy - Beyond the Abstract

Aggressive reduction of prostate and seminal vesicle (SV) planning target volume (PTV) margin while maintaining adequate target coverage can decrease dose to surrounding normal structures such as the rectum and bladder and improve toxicity profile. It is one of the most active areas of research in delivering stereotactic body radiation therapy (SBRT) for prostate cancer. For example, HYPO-RT-PC trial used a 7 mm isotropic planning margin,and the more recent PACE-B trial, which more closely reflected modern SBRT technique, used a tighter 4-5 mm isotropic margin (except 3-5 mm posteriorly).2 Indeed, when directly comparing acute grade ≥2 RTOG genitourinary (GU) toxicity, the rates were lower in PACE-B than HYPO-RT-PC (20.2% vs 28%).1,2 This is likely at least in part due to smaller margin. However, most published reports were not able to further decrease the margin to less than 3mm without compromising target dose coverage. In our study, we aimed to push the envelope further by determining whether a 2mm PTV margin is feasible with SBRT delivered on an MRI-guided linear accelerator (MR-Linacs) from a dosimetric standpoint.


One interesting and somewhat unexpected finding was the extent of prostate swelling during the course of SBRT. In contrast to conventionally fractionated RT in which generally a decrease in prostate volume is expected at the end of treatment, a handful of recent studies hinted that the prostate may actually swell during SBRT.3,4 However, these changes were not rigorously studied and tracked after each fraction. In our study, we analyzed the onboard MRI images before each treatment fraction and observed a substantial increase in prostate volume during the course of SBRT. The prostate volume consistently increased after the first and second fraction, then plateaued and even decreased slightly by the end of RT (still higher than baseline). For the fraction that had the maximum swelling, compared to simulation MRI, the percentage of volume increase ranged from 5.2% to 34.1%, with a median of 16.3%. This degree of change was rather striking. Interestingly, this was not associated with baseline prostate volume. In addition, patients who started on neoadjuvant ADT before SBRT had significantly reduced prostate swelling. One unpublished observation was that the degree of swelling was not correlated with the degrees of change in urinary symptom burdens (such as IPSS score) during treatment although we did not take into account α receptor antagonist use such as tamsulosin during RT.

A key finding was that the dose coverage of the prostate was satisfactory with a 2mm margin despite the degree of swelling observed and also taking into account intrafraction rotation of the prostate (which was quite minimal). Median V100%, V95%, D95% and mean dose of the prostate clinical target volume (CTV) was 97.5%, 99.9%, 40.3Gy and 41.4Gy, respectively (prescription dose was 40Gy in 5 fractions).

Does that mean a 2mm PTV prostate margin should be used as a standard for MRI-guided SBRT? No, not yet. In this report, we focused on interfraction motion of the prostate while one may ask how intrafraction motion affects prostate coverage. One feature that was integral to our treatment delivery was real-time cine MRI imaging which enabled direct soft-tissue-based gating of beam delivery. It automatically pauses the beam when the prostate moves out of the 3mm gating boundary. The precise dosimetric impact of intrafraction motion is actively under investigation and we are planning to report it separately in the future.

In contrast to the prostate, the story for proximal SV was quite different. We did observe an increase in the proximal SV volume during SBRT with the caveat that precise proximal SV volume assessment was challenging given its small size and deformable nature. However, more importantly, proximal SV exhibited robust interfraction rotation. A median change of 21.5° was observed in terms of the angle between the two lobes of proximal SV on the axial plane. Similarly, in the sagittal plane, the change of pitch of the proximal SV had a median of 17.6°. As a result, the dose coverage of the proximal SV was sub-optimal. In only 59% of the fractions, at least 95% of the target volume received at least 95% of the prescription dose. Our exploratory analysis showed that a margin of 5mm circumferentially and 7mm in the posterior direction was required to achieve at least 90% coverage of proximal SV CTV in at least 4 out of 5 fractions, for at least 90% of the patients. In real clinical practice, this large margin would not be feasible.

The take-home message of the study is that prostate dosimetry was favorable with a 2mm planning margin despite substantial swelling observed during the course of SBRT, but online adaptive therapy may be indicated occasionally to account for prostatic swelling and in particular proximal SV rotations.

Several questions remain to be answered. Despite consistent swelling early on in the course of SBRT, the extent of swelling varied considerably across patients. What is the underlying mechanism and can we predict the extent of swelling for a given patient in an effort to tailor the margin to that particular patient? The answer is unknown at the moment, but we suspect immune responses may be at play. Another unanswered question is whether the suboptimal proximal SV dose coverage will indeed lead to worse clinical outcomes. We did prescribe the proximal SV to a full dose of 40Gy in 5 fractions but can we get by with a low dose? Last but not least, it remains to be proven that this decreased margin will lead to improved GU and gastrointestinal toxicity related to the RT. The MIRAGE trial (NCT04384770), a randomized phase III trial specifically comparing acute GU toxicity with MRI-guided SBRT vs. CT-guided SBRT, has completed accrual. We are eagerly waiting for the initial toxicity results which would be instrumental in answering this question.

Written by: Martin Ma, MD, PhD, Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, CA, United States

References:

  1. 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. Lancet (London, England). 2019;394:385-95.
  2. Brand DH, Tree AC, Ostler P, van der Voet H, Loblaw A, Chu W, et al. Intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): acute toxicity findings from an international, randomised, open-label, phase 3, non-inferiority trial. The Lancet Oncology. 2019;20:1531-43.
  3. Gunnlaugsson A, Kjellén E, Hagberg O, Thellenberg-Karlsson C, Widmark A, Nilsson P. Change in prostate volume during extreme hypo-fractionation analysed with MRI. Radiat Oncol. 2014;9:22.
  4. Willigenburg T, de Muinck Keizer DM, Peters M, Claes A, Lagendijk JJW, de Boer HCJ, et al. Evaluation of daily online contour adaptation by radiation therapists for prostate cancer treatment on an MRI-guided linear accelerator. Clin Transl Radiat Oncol. 2021;27:50-6.

Read the Abstract
email news signup