Abstract
Objective:
The most commonly used dose for prostate cancer stereotactic body radiotherapy (SBRT) is 5 × 7.25 Gy. The aim of this study was to evaluate the dosimetric feasibility of a 5 × 9 Gy SBRT regimen while still limiting the dose to the urethra to 5 × 7.25 Gy. This dosimetric study is part of the groundwork for a future Phase III randomized trial.
Methods:
The prostate, the urethra and the tumors were delineated on 20 dosimetric CT-scans with MRI-registration. The planning target volume (PTVp) was defined as a 5 mm expansion (3 mm posteriorly) of the prostate. The planning at risk volume (PRVu) was defined as a 2 mm expansion of the urethra. The tumors were delineated on the MRI (GTVt) and a 3 mm-margin was added to create a tumoral planning target volume (PTVt). IMRT plans were optimized to deliver 5 × 9 Gy to the PTVp, limiting the dose to the PRVu to 5 × 7.25 Gy. Results are presented using average (range) values.
Results:
PTVp doses were D98% = 36.2 Gy (35.6–36.8), D2% = 46.9 Gy (46.5–47.5) and mean dose = 44.1 Gy (43.8–44.5). The dose to the PRVu was within tolerance limits for all 20 patients: V34.4Gy = 99.8% (99.2–100) and D5% = 38.7 Gy (38.6–38.8). Dose coverage of PTV-PRVu was D95% = 40.6 Gy (40.5–40.9), D5% = 46.6 Gy (46.2–47.2) and mean dose = 44.6 Gy (44.3–44.9). Dose to the PTVt reached 44.6 Gy (41.2–45.9). Doses to the OAR were respected, except V36Gy ≤1 cc for the rectum.
Conclusion:
A SBRT dose-escalation to 5 × 9 Gy on the prostate while sparing the urethra + 2 mm at 36.25 Gy is feasible without compromising dose coverage to the tumor. This radiation regimen will be used for a Phase-III trial.
Advances in knowledge:
In prostate SBRT, dose optimization on the urethra is feasible and could decrease urinary toxicities.
Introduction
Stereotactic body radiation therapy (SBRT) is becoming a standard of care for localized prostate cancers (PCa).1 The most common regimen today delivers 36.25 Gy in 5 fractions (fx) of 7.25 Gy.2 At this dose, urinary and rectal adverse events are rare. Kishan et al.’s long-term outcomes of SBRT for 2142 low-risk (LR) and intermediate-risk (IR) PCa patients reported a 7 year incidence of late Grade 3 or higher genitourinary (GU) and gastrointentinal toxicities of only 2.4 and 0.4%, respectively.3 However, the rates of biochemical recurrence after 7 years of follow-up reached 14.9% for unfavorable IR disease, raising the question for SBRT dose escalation.
In 2018, Zelefsky et al increased the prescribed dose above 36.25 Gy in 5 fx in a SBRT Phase I trial that enrolled 136 patients with LR and IR PCa. This study showed that both local control and toxicities proportionally increased with dose levels.4 Late urinary Grade 2 toxicities were 23.3%, 25.7%, 27.8% and 31.4% at 32.5, 35, 37.5 and 40 Gy, respectively. 5-year biochemical recurrence rate was 0% delivering 37.5 and 40 Gy (5 × 7.5 and 5 × 8 Gy) compared to 15 and 6% at 32.5 and 35 Gy. Moreover, the 2 year positive biopsy rate decreased with the prescribed dose but remained at 7.7% at 40 Gy, suggesting that the optimal dose could not be reached.
In a Phase I/II trial published in 2016 by Hannan et al, doses up to 50 Gy in 5 fractions resulted in excellent biochemical control rates at 5 years. Freedom from biochemical failure was 90.9% at 45 Gy and 100% at 47.5 and 50 Gy. However, patients in the 50 Gy arm displayed high rates of Grade 2 and 3 GU toxicities, with 1.6 and 3.3% late Grade 4 GU and GI toxicities, respectively. Thus, the authors suggested that doses be kept under 50 Gy.5 Potters et al.’s SBRT dose escalation trial also showed that a significantly lower PSA nadir could be achieved with 45 Gy or 50 Gy compared to 40 Gy.6
Urinary toxicity following SBRT has been extensively studied. According to the Georgetown experience, a flare in urinary symptoms (dysuria, frequency and urgency) occurred in 13.4% of patients, with a peak between 6 and 18 months after treatment. This was reported as a significant problem by 42.9% of patients.7 Correlation between urinary toxicity and dosimetric parameters such as the maximum dose (Dmax) to the urethra, urethral volume receiving 44 Gy (V44 Gy), and large prostate and bladder volumes have also been reported. In 2016, Repka et al reported their experience of 102 patients treated with a dose of 35–36.25 Gy in 5 fractions. The maximum point dose of the prostatic urethra was restricted to 40 Gy. Using those constraints, acute urinary bother rates were close to those seen after conventionally fractionated EBRT.8
Literature data tend to show that 36.25 Gy is an appropriate dose to avoid urinary side-effects but might not be sufficient to ensure proper local control, especially for high-intermediate risk prostate cancer. Moreover, escalating the total dose may allow a higher local control at the cost of increased urinary and rectal toxicities. However, the risk of rectal toxicities can be significantly lowered using a spacer.9 The aim of the present study was to evaluate the dosimetric feasibility of a 5 × 9 Gy SBRT regimen while still limiting the dose to the urethra to 5 × 7.25 Gy. This dosimetric study is part of the groundwork for a future Phase III randomized trial.
Methods and materials
Eligibility criteria
This dosimetric analysis was performed on 20 planning CT-scans of patients who have been treated for a PCa in our department. All patients had gold markers implanted before the CT-scan and a MRI registration was performed. Exclusion criteria were: prior transurethral resection of the prostate and hip prothesis.
CT-MRI image registration
MRI T1- and T2 weighted sequence images were matched with the planning CT-scans using the gold markers implanted in the prostate.
Target volumes and organs delineation
All the volumes were delineated by the same radiation oncologists (SB and OC), with the help of a radiologist with prostate MRI expertise (OR).
The prostate was delineated without the seminal vesicles. The planning target volume (PTVp) was an automatic expansion of the prostate with a 5 mm margin in all directions, except for the posterior margin, which was reduced to 3 mm.
The prostatic urethra was delineated on registered T2 weighted MRI images, starting from the vesical trigone down to 1 cm under the apex of the prostate. The urethral planning at risk volume (PRVu) was an automatic expansion of the urethra with a 2 mm margin in all directions.
Tumors with 3 to 5 PIRADS score were also delineated (GTVt) and a tumoral planning target volume (PTVt) was then defined as an 3 mm expansion of the GTVt.
The rectum was delineated from just above the anorectal junction to the rectosigmoid junction. The bladder was delineated from the base to the dome. Both organs at risk were delineated as a whole, with both the lumen and the organ wall. The femoral head delineation was performed from the top down to one slice below the lesser trochanter.
Treatment planning
Treatment plans were generated using the Eclipse® software (Varian). Planning was performed with an Analytical Anisotropic Algorithm model of a Flattening Filter 6 MV X-ray beam, from a Novalis Truebeam accelerator with a high-definition multileaf collimator. Each plan was performed on volumetric modulation arctherapy with three coplanar arcs (collimator rotation 45°, 315° and 40°) and a dose rate of 600 monitor units (MU) per minute. Average MU was 1000 MU per arc, reaching approximately 3000 MU per fraction.
RapidArc® was used to deliver 5 × 9 Gy to the PTVp, with an optimized dose of 5 × 7.25 Gy (PRVu) to the urethra.
Optimisation contraints for the PTVp, PRVu and PTV-PRVu and organs-at-risk dose constraints10 are summarized in Table 1.
Table 1.
Dosimetric contraints and optimization results as average (range) for OAR and for the target volumes
| Volume | Contraints | Optimization results | |
|---|---|---|---|
| OAR | |||
| Rectum | |||
| D50% (Gy) | <18.1 | 8.8 (1.9–15.4) | |
| D20% (Gy) | <29 | 17.7 (13–28.2) | |
| V36Gy (cc) | ≤1 | 2.8 (0.2–5.9) | |
| Bladder | |||
| D40% (Gy) | <18.1 | 5.8 (0.8–16.5) | |
| V37Gy | <10 | 6.7 (2.3–14.2) | |
| Femoral heads | D5% (Gy) | <14.5 | 11.7 (8.4–14) |
| Targets | |||
| PRVu (5 × 7.5 Gy) | |||
| V34.4Gy (%) | ≥99% | 99.8 (99.2–100) | |
| D5% (Gy) | <38.8 | 38.7 (38.6–38.8) | |
| Mean dose (Gy) | <38.8 | 36.9 (36.6–37.3) | |
| PTVp (5 × 9 Gy) | |||
| D98% (Gy) | <46 | 36.2 (35.6–36.8) | |
| D2% (Gy) | <47.25 | 46.9 (46.5–47.5) | |
| Mean dose (Gy) | >42.75 | 44.1 (43.8–44.5) | |
| PTVp – PRVu (5 × 9 Gy) | |||
| D95% (Gy) | ≥40.5 | 40.6 (40.5–40.9) | |
| D5% (Gy) | <48.15 | 46.6 (46.2–47.2) | |
| Mean dose (Gy) | >42.75 | 44.6 (44.3–44.9) | |
OAR, organ at risk; PRV, planning at risk volume; PTV, planning target volume.
According to the RTOG definitions, the conformity index (CI), homogeneity index (HI) and gradient index (GI) were also reported for PTVp-PRVu and PRVu.11
No specific optimisation constraints were used for the GTVt and the PTVt, but dose coverage of both structures was recorded.
Results
Prostate and tumor characteristics
Average (range) prostatic and PTVp volumes were 45.2 cc (21.9–102) and 82.4 cc (49.2–172), respectively.
27 target lesions (GTVt) were identified on MRI images: 7 lesions (26%) were scored PIRADS 3, 10 lesions (37%) PIRADS 4 and 10 lesions (37%) PIRADS 5. The mean number of tumoral targets per patient was 1.35 with a maximum of three tumoral targets in one patient. Two patients (10%) had no visible tumor on the MRI. The average (range) tumor volume was 1.5 cc (0.2–11.6). Tumor location and characteristics according to the PIRADS classification are available in Table 2.
Table 2.
PIRADS tumoral targets’s characteristics (n = 27) and average (range) volumes
| PIRADS 3 | PIRADS 4 | PIRADS 5 | Total | ||
|---|---|---|---|---|---|
| n (%) | 7 (26%) | 10 (37%) | 10 (37%) | 27 (100) | |
| Volume (cc) | |||||
| GTVt | 0.5 (0.02–1.3) | 0.8 (0.1–2.5) | 2.9 (0.9–11.6) | 1.5 (0.02–11.6) | |
| PTVt | 2.5 (1.03–4.7) | 3.2 (1.3–7.4) | 7.8 (2.1–25.5) | 4.7 (1.03–25.5) | |
| Localization n (%) | |||||
| Apex | 5 (71.4) | 1 (10) | 1 (10) | 8 (29.7) | |
| Apex–Midzone Junction | 1 (14.3) | 6 (60) | 2 (20) | 9 (33.3) | |
| Base | 0 (0) | 3 (30) | 4 (40) | 6 (22.2) | |
| All prostate’s height | 0 (0) | 0 (0) | 2 (20) | 2 (7.4) | |
| AFMS | 0 (0) | 0 (0) | 1 (10) | 1 (3.7) | |
| Central zone (paraurethral) | 1 (14.3) | 0 (0) | 0 (0) | 1 (3.7) | |
AFMS, anterior fibromuscular stroma; GTV, gross tumor volume; PTV, planning target volume.
Volume coverage and conformity index
All the results are listed in Table 1. Dose constraints for the PTVp, PRVu and PTVp-PRVu, were met in all the cases, except for the PTVp D2% which slightly exceeded 47.3 Gy in two cases (47.5 Gy and 47.3 Gy).
Conformity index, HI and GI for PTV-PRVu and PRVu were consistent with the SBRT standard guidelines.11 For the PTV-PRVu, average (range) CI was 1.08 (1.03–1.1), HI was 1.08 (1.06–1.1), and GI reached 3.4 (3.3–3.6). For the PRVu, average (range) HI was 1.1 (1.1–1.2) and GI was 3.3 (2.98–3.5).
Axial (left) and sagittal (right) slices of a prostatic SBRT dosimetry delivering 5 × 9 Gy with urethral optimization at 5 × 7.25 Gy are depicted in Figure 1.
Figure 1.
Axial (left) and sagittal (right) slices of a prostatic SBRT dosimetry, delivering 5 × 9 Gy with urethral preservation at 5 × 7.25 Gy. SBRT, stereotactic body radiotherapy
PIRADS target coverage
The results of PIRADS targets coverage for GTVt and PTVt are available in Table 3.
Table 3.
Dosimetric parameters of PIRADS targets expressed in average (range)
| GTVt | PTVt | |
|---|---|---|
| D100% (Gy) | 40.7 (34.7–45.2) | 37.8 (27.2–43.8) |
| V45Gy (%) | 64 (7.8–100) | 55.8 (16.2–87.9) |
| V42.75Gy (%) | 92.3 (29–100) | 88.7 (40.9–100) |
| Mean dose (Gy) | 45 (39.9–46.4) | 44.6 (41.2–45.9) |
GTV, gross tumor volume; PTV, planning target volume
GTVt volume receiving 42.75 Gy (95% of 45 Gy) was 100% in 11 targets, over 95% in 19 targets and greater or equal to 90% in 21 targets.
PTVt volume receiving 42.75 Gy was equal to 100% in 4 targets, over 95% in 11 targets and greater or equal to 90% in 12 targets.
Doses to organs at risk
Dosimetric optimization results for OAR are summarized in Table 1.
The average (range) rectal volume was 65.4 cc (38.7–121.2) and mean dose was 11.4 Gy (range: 7.9–17.5). D50% < 18.1 Gy and D20% < 29 Gy were met for all patients. On the other hand, V36Gy ≤1 cc was only met for one of the 20 patients (V36Gy = 0.2 cc). Average rectal volumes (cc) receiving 80%, 90% and 100% of the total dose were respectively 2.8 cc (0.2–5.9), 1.6 cc (0.0–4.1) and 0.05 cc (0.0–0.3).
The average (range) bladder volume was 223.1cc (71.5–593.6) and mean dose was 8.4 Gy (range: 2.3–16.7). D40% < 18.1 Gy was met for all 20 cases and V37Gy ≤10 cc for 16 of them. The four patients for whom this constraint could not be kept had a V37Gy equal to 11.9, 14.2, 11.7 and 11.5cc.
D5% < 14.5 Gy for both femoral heads was achieved for all patients.
Discussion
High biochemical control of prostatic disease can be achieved in many SBRT dose-escalation studies.1,4 However, in these studies, rectal and urinary side-effects increased with total prescribed dose.5 In order to prevent urinary toxicities, the present study suggests an innovative approach to limit the dose to the urethra (36.25 Gy) while escalating the dose to the rest of the prostate (45 Gy), with a dose report to every single tumoral target.
Urethral sparing and urinary toxicity
In order to prevent urinary events, Repka et al restricted the maximum point dose of the prostatic urethra to 40 Gy and used systematic prophylactic alpha-adrenergic antagonists in their SBRT trial (35–36.25 Gy/5 fx).8 An acute flare-up of urinary symptoms was seen at 1 week and 1 month before returning to baseline at 3 months. The bladder wall D15.5% (OR1.62, 95% CI 1.02–2.59, p = 0.043) was an independent prognostic factor for urinary symptoms.
Bruynzeel et al used daily plan adaptation with MRI-guidance to deliver 5 × 7.25 Gy to the PTV while sparing the urethra to a dose of 5 × 6.5 Gy.12 Despite a rather short follow-up, they reported no early Grade 3 GU (or GI) toxicity and only 19.8% of Grade 2 GU toxicity. Unfortunately, dosimetric results for OARs are not reported in their study.
McDonald et al delivered 36.25 Gy/5 fx with an integrated boost of 40 Gy to the tumors segmented on the MRI images.13 Prostatic PTV was covered by the 34.4 Gy isodose. The urethra maximum point dose was 38.78 Gy. In this study, urinary retention incidence was 7.7%. Grade 2 GU toxicities were as follows: dysuria: 11.5%, frequent urination: 15.4% and urinary hesitancy: 19.2%.
Zilli et al published a Phase II trial with 5 × 7.25 Gy to the prostate and 5 × 6.5 Gy to the urethra and reported 18 months follow-up results, comparing once-a-week vs every-other-day radiation deliverance. At 18 months, grade ≥2 GU and GI toxicity decreased below 2% and 5% for both arms, respectively, showing low toxicity profile and favorable biochemical rates regardless of overall treatment time.14
Jaccard et al stated that use of VMAT - which is the technique we used in the present study - yielded better dosimetric results for preserving urethra than IMRT and also gave less protocol violations. Moreover, including seminal vesicles increased rectal’s wall dosimetry, while we only contoured the prostatic gland.15
All these studies suggest that an urethral sparing approach is feasible. However, none of those used a dose to the PTV over 40 Gy. In our study, with a 5 × 9 Gy dose to the PTV, a similar maximum dose constraint to the urethra was successfully applied (D5% < 38 Gy) and met, displaying the potential safety of our radiation regimen.
Due to multiplanar capability and excellent tissue contrast, MRI provides anatomic details about the urethra, periurethral tissues and the orientation of the urethra. It uses T1- and T2 weighted imaging to evaluate urethra in orthogonal planes (axial, sagittal, and coronal), or imaged obliquely along its course.
Thin slices (3–5 mm) and a small interslice gap (1–2 mm) are desirable for imaging the urethra. On axial images, the prostatic urethra is seen in the central portion of the posterior prostatic gland. However, the proximal portion of the prostatic urethra is rarely visualized on MR images unless a Foley catheter is placed, which was not the case in the present study.
Macroscopic tumor dose coverage
Some authors argue that sparing the urethra could result in insufficient treatment of paraurethral prostate tumors. For instance, Vaishtein et al.’s normofractionated IMRT trial compared a urethral sparing method to a conventional approach and showed inferior biochemical control with urethral-sparing.16 In the present study, 99% of the PRVu received doses greater or equal to 34.4 Gy (95% of 36.25 Gy), which met our initial objective. Moreover, most tumors were located in the prostate’s peripheral zone and were comprised in the 45 Gy isodose. As such, the present radiation regimen should insure a local control rate at least equal to the current worldwide standard SBRT dose of 36.25 Gy in 5 fractions of 7.25 Gy. Then again, the dose escalation reached in a majority of our tumors should lead to an improvement in local control.
Rectal toxicity and spacers
Both conventionally fractionated radiotherapy and SBRT studies have shown that higher doses to the rectum is correlated with increased rectal toxicity.17,18
A previous study demonstrated that hyaluronic acid injections significantly reduced the dose to the rectal wall and allowed dose escalation from 5 × 6.5 Gy to 5 × 8.5 Gy without increasing the dose to the rectum.9 The average volume of the rectal wall covered by the 90% isodose (V90%) was reduced by 90% with the injection. The reduction of dose received by the rectal wall after the injection was significant in its portion facing the middle to the apex of the prostate (p = .002).
With hydrogel spacer, Hwang et al did not report any acute rectal toxicity over 1 month after their 36.25 Gy / 5 fx treatment.19 The D50% < 18.1 Gy to the rectum was one of the rectal constraints used in their study as well as in ours. Using a rectal spacer, their D50% to the rectum was 13.5 Gy. In the present study, the V36Gy ≤1 cc rectal constraint was only met for one of the 20 patients, whose anterior rectal wall was further from the prostate. Using a spacer, this constraint was successfully upheld for all patients in Hwang et al.’s study.
The use of transperineally injected rectal spacers appears to be an interesting option to keep apart the anterior rectal wall from the prostate and meet the V36 constraint, especially in a dose escalation to 5 × 9 Gy.
Conclusion
This dosimetric study confirms that a 45 Gy SBRT dose-escalation to the prostate while sparing urethra at the dose of 36.25 Gy is feasible. Dose optimization to the urethra + 2 mm may allow for a urinary toxicity profile close to the standard 5 × 7.25 Gy SBRT regimen. Lower rectal dose constraints could be reached with a spacer between the rectum and the prostate. Despite this urethral sparing, doses received to GTVt and PTVt remained close to the escalated dose (5 × 9 Gy) in most cases. This study thus endorses a SBRT regimen which will be used in a future Phase III randomized trial.
Contributor Information
Salim Benhmida, Email: salimbenhmida10@gmail.com.
Amandine Beneux, Email: amandine.beneux@chu-lyon.fr.
Corina Udrescu, Email: corina.udrescu@hotmail.com.
Olivier Rouviere, Email: olivier.rouviere@chu-lyon.fr.
Samy Horn, Email: samy.horn@chu-lyon.fr.
Ciprian Enachescu, Email: ciprian.enachescu@chu-lyon.fr.
Ariane Lapierre, Email: ariane.lapierre@chu-lyon.fr.
Olivier Chapet, Email: olivier.chapet@chu-lyon.fr.
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