Impact of daily soft‐tissue image guidance to prostate on pelvic lymph node (PLN) irradiation for prostate patients receiving SBRT

Abstract Purpose To determine the impact of using fiducial match for daily image‐guidance on pelvic lymph node (PLN) coverage for prostate cancer patients receiving stereotactic body radiation therapy (SBRT). Methods Thirty patients underwent SBRT treatment to the prostate and PLN from 2014 to 2016. Each patient received either 800cGy × 5 or 500cGy × 5 to the prostate and 500cGy × 5 to the PLN. A 5 mm clinical target volume (CTV)‐to‐planning target volume (PTV) margin around the PLN was used for planning. Two registrations with planning computed tomography (PCT) for each of the daily cone beam CTs (CBCTs) were performed: a rigid registration to fiducials and to the bony anatomy. The average translational difference between fiducial and bony match as well as percentage of fractions with differences > 5mm were calculated. Changes in bladder and rectal volume as well as center‐of‐mass (COM) position from simulation parameters, and their correlation with translational difference were also evaluated. The dosimetric impact of the translational differences was calculated by shifting the plan isocenter. Results The average translational difference between fiducial and bony match was 0.06 ± 0.82, 2.1 ± 4.1, −2.8 ± 4.3, and 5.5 ± 4.2 mm for lateral, vertical, longitudinal, and vector directions. The average change in bladder and rectal volume from simulation was −67.2 ± 163.04 cc (−12 ± 52%) and −1.6 ± 18.75 (−2 ± 30%) cc. The average change in COM of bladder from the simulation position was 0.34 ± 2.49, 4.4 ± 8.1, and −3.9 ± 7.5 mm along the LR, AP, and SI directions. The corresponding COM change for the rectum was 0.17 ± 1.9, 1.34 ± 3.5, and −0.6 ± 5.2 mm. Conclusions The 5 mm margin covered ~75% of fractions receiving PLN irradiation with SBRT, daily CBCT and fiducial‐guided setup. The dosimetric impact on PLN coverage was significant in 19% of fractions or 25% of patients. A larger translational shift was due to variation in rectal volume and changes in COM position of the bladder and rectum. A consistent bladder positioning and/or rectum filling compared with presimulation volume were essential for adequate coverage of PLN in a hypofractionated treatment regime.

compared with presimulation volume were essential for adequate coverage of PLN in a hypofractionated treatment regime.

K E Y W O R D S
image guidance, pelvic lymph node, prostate cancer, stereotactic body radiation therapy 1 | INTRODUCTION Radiotherapy (RT) is a commonly used modality for the treatment of prostate cancer. Patients with high-risk prostate cancer, which is defined by the National Comprehensive Cancer Network as having at least one adverse feature (T3a or higher; Gleason score 8-10, or prostate-specific antigen > 20 ng/mL), have an increased risk for nodal involvement. 1 Therefore, it is recommended that pelvic lymph nodes (PLN) be included in the target volume for those patients. In addition, there is evidence of clinical benefit from PLN treatment in the high-risk population. 2,3 Given the low α/β ratio attributed to prostate cancer, (approximately 1.5-1.8), hypofractionation is potentially more beneficial for occult nodal metastases in high-risk patients. 4 At our institution, high-risk prostate patients with Gleason score > 8 are considered to undergo PLN external beam irradiation.
Because more accelerated courses of moderate and ultra-hypofractionation RT are currently being used for prostate treatments, evaluating the role of PLN treatment with hypofractionation continues.
The ongoing phase II SATURN trial (NCT01953055), assessing the toxicity and clinical outcomes of 500 cGy per fraction to pelvic nodes, has finished accrual; a report of the initial outcomes is expected in 2019. Several small, preliminary trials have been reported, evaluating the feasibility and safety of this approach. [5][6][7][8] At our institution, hypofractionated PLN RT is done in specific cases, and the urinary and bowel toxicity of 21 patients treated with PLN hypofractionation was recently evaluated. At this point, with a median follow-up of 9 months, urinary and gastrointestinal toxicities were evaluated, which will be reported in a future study. Preliminary assessments indicate that stereotactic body radiation therapy (SBRT) to PLNs given in five fractions (for a total dose of 25 Gy) using dose painting to the prostate and seminal vesicles is safe and well tolerated without increased rates of gastrointestinal toxicity. However, longer follow-up is required to assess the efficacy of this treatment as well as its effect on biochemical control.
It is well known that the PLN are relatively fixed with respect to the pelvic vasculature, or the nearby bony anatomy, and move independently of the prostate. This raises the question of adequacy of PLN coverage when the image-guided setup based on a prostate fiducial match is utilized for patients undergoing intensity modulated radiation therapy. This has been extensively studied for conventional fractionation, and it has been concluded that over a conventionally fractionated course of treatment, random shifts will provide adequate coverage that is unlikely to result in impactful underdosing. [9][10][11][12] However, limited studies with small number of patients exist regarding pelvic node coverage using SBRT. 13 In this scenario, in addition to systematic errors, random errors may also have a large negative impact. 14 The purpose of this study was to assess PLN coverage based on prostate fiducial matching during daily SBRT treatment.

| MATERIALS AND METHODS
Thirty intact gland prostate patients who underwent five fraction SBRT treatment to the prostate and PLN from 2014-2016 were evaluated in this IRB-approved study. Each patient received either 800 cGy × 5 fx or 500 cGy × 5 fx to the prostate and 500 cGy × 5 fx to PLN. Pelvic CTV lymph node volumes were delineated up to aortic bifurcation by placing a 7 mm margin around the vessels, carving out bowel, bladder, and bone tissue, as per Radiation Therapy Oncology Group genitourinary radiation oncology specialists consensus. 15 There are currently no guidelines for PLN hypofractionation, and the same margins around the vessels to generate clinical target volume (CTV) lymph nodes when moving from a conventional to a hypofractionation scenario have been used. Additionally, a 5 mm margin around the CTV was used to create the planning target volume (PTV) to account for day-to-day setup variation. Prostate CTV volume included entire prostate and bilateral seminal vesicles. A uniform 5 mm margin around the prostate CTV except a 3 mm margin at the prostate-rectal interface was used to create the prostate PTV.
All patients were treated on Varian TM linear accelerator and positioned using the on-board cone beam CTs (CBCT).  used only if there was gas in the rectum) were used for both CT and MR simulation. Three gold fiducial markers of 3 mm length and 1.2 mm diameter were implanted into the prostate under ultrasound guidance roughly 2 weeks prior to simulation. These markers were used to confirm and monitor the prostate position before and during each SBRT treatment using image guidance. During treatment, CBCTs were acquired for initial image-guided setup. Each patient underwent five CBCT acquisitions. Daily CBCTs were also used to assess adequate bladder and rectum filling. Coefficients with P < 0.05 were considered statistically significant.

2.B | Image analysis
The coefficient values and the strength of association was calculated using general guidelines provided by Cohen et al. 16 as shown in Table 1.   Table 2 Table 3   Daily variations in rectal volume as well as changes in COM position of the bladder and rectum were correlated with the translational shifts. Our bowel prep protocol includes using GasX/enema the night before and on the day of the treatment. Patients are also instructed to drink one cup (or~235 ml)/45 min, but patient queue and machine delays may add to the variation in bladder filling. The bladder and rectal volumes were also systematically smaller than the simulation volume for the majority of patients. Although a much larger variation in bladder volume was observed compared with rectal volume, the change in bladder volume was not correlated with the translational shifts. We believe changes in bladder volume might push the bladder anteriorly and superiorly but with a lesser effect on the actual prostate. The change in COM of rectum was more strongly correlated with translation shifts as compared to change in COM of bladder.

3.C | Dosimetric impact
Finally, our study supports the inclusion of PLN in CBCT scans during daily image guidance for SBRT cases by shifting the couch longitudinally by approximately 5 cm. Physicians reviewing the daily CBCT scans should also look at PLN coverage in addition to prostate coverage, and if a large discrepancy is observed, it should be investigated before proceeding with the treatments.

| CONCLUSION S
Our study indicates that a 5 mm margin provides coverage for~75% of patients receiving PLN irradiation with SBRT, daily CBCT and fiducial-guided setup. In 19% of fractions or 25% of patients, the dosimetric impact on PLN coverage was significant. The largest translational shifts were seen in the vertical and longitudinal directions and were due to variation in rectal volume as well as changes in COM position of the bladder. This indicates that consistent bladder positioning and/or rectum filling compared with volumes at simulation is essential for adequate coverage of PLN in a hypofractionated treatment regime.

ACKNOWLEDG MENTS
This research was partially supported by the NIH/NCI Cancer Center Support Grant/Core Grant (P30 CA008748). We are grateful to Mr.
James Keller for his help in editing this manuscript.

CONFLI CT OF INTERESTS
None.